Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders

ABSTRACT

Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders using the oral cannabinoid pharmaceutical compositions are described.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application63/143,320 filed Jan. 29, 2021, the contents of which are hereinincorporated by reference in their entirety.

TECHNICAL FIELD

The present disclosure relates to oral cannabinoid pharmaceuticalcompositions and methods of treating sleep disorders using the oralcannabinoid pharmaceutical compositions.

BACKGROUND

The Centers for Disease Control and Prevention have declaredinsufficient sleep a public health problem. It is recommended thatadults get at least 7 hours of sleep per night for optimal health andwellbeing (Watson et al., Sleep. 2015 Aug. 1; 38(8):1161-83). However,one-third of US adults report getting less than 7 hours of sleep pernight and up to 70 million suffer from sleep disorders (Liu Y et al.,Morb Mortal Wkly Rep. 2016 Feb. 19; 65(6):137-41; National Heart, Lung,and Blood Institute, National Sleep Disorders Research Plan, 2003.Bethesda, Md.: National Institutes of Health; 2003). Insufficient sleepis associated with a plethora of adverse health conditions includingdiabetes, hypertension, heart disease, stroke, depression, obesity,impaired immune function and increased risk of death (Watson et al.,Sleep. 2015 Aug. 1; 38(8):1161-83). Existing sleep aids can often beineffective or only marginally effective, and some may have a profounddeleterious impact on quality of sleep, in particular on REM sleep anddeep sleep components of the sleep experience. However, development ofimproved sleep medications is challenging.

SUMMARY

According to a first aspect, the present disclosure relates provides anoral pulse-release dosage form, comprising a total daily dose of a firstcannabinoid active pharmaceutical ingredient (API₁) and a total dailydose of a second cannabinoid API (API₂). The oral pulse-release dosageform comprises a first pulse-release component (C₁) comprising a firstportion (P₁) of the first cannabinoid API (API₁P₁) and a first portion(P₁) of the second cannabinoid API (API₂P₁). The oral pulse-releasedosage form also comprises at least a second pulse-release component(C₂) comprising a second portion (P₂) of the first cannabinoid API(API₁P₂) and a second portion (P₂) of the second cannabinoid API(API₂P₂). The total daily dose of each of the API₁ and the API₂ isdivided between the first portion (P₁) in the first pulse-releasecomponent (C₁) and at least the second portion (P₂) in the at leastsecond pulse-release component (C₂). When the pulse-release dosage formis placed in an aqueous solution of 0.1N HCl pH 1.1 for 2 hours followedby 8 hours in sodium phosphate buffer at pH 6.8, at 37° C.±0.5° C., thepulse-release dosage form provides release of the API₁P₂ and the API₂P₂beginning from 2 to 6 hours after release of the API₁P₁ and the API₂P₁begins.

The oral pulse-release dosage form may include the following details,which can be combined with one another in any combinations unlessclearly mutually exclusive:

The pulse-release dosage form may provide a second time of peak releaserate (PRR₂) of each of the API₁ (PRR₂API₁) and the API₂ (PRR₂API₂) fromabout 2 to 6 hours after a first time of PRR (PRR₁).

The PRR₁ may be after 1-2 hours.

The first cannabinoid API₁ may be delta-9-tetrahydrocannabinol (THC) andthe second cannabinoid API₂ may be cannabinol (CBN). The total dailydose of the THC may be from 1 mg to 40 mg and the total daily dose ofthe CBN may be from 2.5 mg to 100 mg.

The first cannabinoid API₁ may be THC and the second cannabinoid API₂may be CBN. The total daily dose of the THC may be selected from: atleast 1 mg, at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg,at least 6 mg, at least 8 mg, at least 10 mg, at least 15 mg, at least20 mg, at least 25 mg, at least 30 mg, and at least 35 mg, and the totaldaily dose of the CBN may be selected from: at least 2.5 mg, at least 3mg, at least 4 mg, at least 5 mg, at least 15 mg, at least 20 mg, atleast 25 mg, at least 30 mg, at least 35 mg, and at least 40 mg, atleast 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, atleast 90 mg, and at least 95 mg.

The first pulse-release component (C₁) may be an immediate release (IR)formulation of the first cannabinoid API₁ and the second cannabinoidAPI₂, comprising: the first portion (P₁) of the first cannabinoid API(API₁P₁) and a first portion (P₁) of the second cannabinoid API(API₂P₁), and one or more binders, one or more disintegrants, one ormore lubricants, one or more flow aids, or any combinations thereof. Thesecond pulse-release component (C₂) may be a delayed release (DR)formulation of the first cannabinoid API₁ and the second cannabinoidAPI₂, comprising: the second portion (P₂) of the first cannabinoid API(API₁P₂) and a second portion (P₂) of the second cannabinoid API(API₂P₂), and one or more binders, one or more lubricants, one or moreflow aids, or any combinations thereof. The second pulse-releasecomponent may be coated with a delayed-release layer comprising one ormore pH-dependent and/or non-pH-dependent polymers, and optionally oneor more plasticizers, one or more pore formers, or one or lubricants, orany combinations thereof.

For each API, the first portion (P₁) may be independently selected from25% to 75% of the total daily dose, and for each API the second portion(P₂) may be independently selected from 25% to 75% of the total dailydose.

In the first pulse-release component (C₁), the second pulse-releasecomponent (C₂), or both, when present: the binders may comprise from 1to 60% (w/w), the disintegrants may comprise from 0.05 to 15% (w/w), thelubricants may comprise from 0.5 to 5% (w/w), the flow aids may comprisefrom 0.05 to 0.5% (w/w), and the pH-dependent and/or non-pH-dependentpolymers may comprise from 0.5 to 35% (w/w).

The first pulse-release component (C₁) may comprise from 0.5 mg to 30 mgof the first cannabinoid active pharmaceutical ingredient (API₁),wherein the API₁ is THC, and from 1.25 mg to 75 mg of the secondcannabinoid active pharmaceutical ingredient (API₁), wherein the API₁ isCBN. The first pulse-release component (C₁) may comprisemicrocrystalline cellulose, hydroxypropylmethylcellulose, and magnesiumstearate. The second pulse-release component (C₂) may comprise from 0.5mg to 30 mg of the first cannabinoid active pharmaceutical ingredient(API₁), wherein the API₁ is THC, and from 1.25 mg to 75 mg of the secondcannabinoid active pharmaceutical ingredient (API₁), wherein the API₁ isCBN. The second pulse-release component (C₂) may comprisemicrocrystalline cellulose, methacrylic acid copolymer, magnesiumstearate, and colloidal silicone dioxide.

According to a second aspect, the present disclosure relates provides anoral pulse-release dosage form, comprising a total daily dose of a firstcannabinoid active pharmaceutical ingredient (API₁) and a total dailydose of a second cannabinoid API (API₂). The pulse-release dosage formcomprises a first pulse-release component (C₁) comprising a firstportion (P₁) of the first cannabinoid API (API₁P₁) and a first portion(P₁) of the second cannabinoid API (API₂P₁), a second pulse-releasecomponent (C₂) comprising a second portion (P₂) of the first cannabinoidAPI (API₁P₂) and a second portion (P₂) of the second cannabinoid API(API₂P₂), and at least a third pulse-release component (C₃) comprising athird portion (P₃) of the first cannabinoid API (API₁P₃) and a thirdportion (P₃) of the second cannabinoid API (API₂P₂). The total dailydose of each of the API₁ and the API₂ may be divided between the firstportion (P₁) in the first pulse-release component (C₁), the secondportion (P₂) in the second pulse-release component (C₂), and at leastthe third portion (P₃) in the at least third pulse-release component(C₃). When the pulse-release dosage form is placed in an aqueoussolution of 0.1N HCl pH 1.1 for 2 hours followed by 8 hours in sodiumphosphate buffer at pH 6.8, at 37° C.±0.5° C., the pulse-release dosageform provides release of the API₁P₂ and the API₂P₂ beginning from 1 to 4hours after release of the API₁P₁ and the API₂P₁ begins, and release ofthe API₁P₃ and the API₂P₃ beginning from 1 to 4 hours after release ofthe API₁P₂ and the API₂P₂ begins.

The oral pulse-release dosage form may include the following details,which can be combined with one another in any combinations unlessclearly mutually exclusive:

The pulse-release dosage form may provide a second time of peak releaserate (PRR₂) of each of the API₁ (PRR₂API₁) and the API₂ (PRR₂API₂) fromabout 1 to 4 hours after a first time of PRR (PRR₁) and a third time ofpeak release rate (PRR₃) of each of the API₁ (PRR₃API₁) and the API₂(PRR₃API₂) from about 1 to 4 hours after the second time of PRR (PRR₂).

The PRR₁ may be after 1-2 hours.

The first cannabinoid API₁ may be delta-9-tetrahydrocannabinol (THC) andthe second cannabinoid API₂ may be cannabinol (CBN). The total dailydose of the THC may be from 10 mg to 40 mg and the total daily dose ofthe CBN may be from 5 mg to 100 mg.

The first cannabinoid API₁ may be THC and the second cannabinoid API₂may be CBN, and the total daily dose of the THC may be selected from: atleast 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30mg, and at least 35 mg, and the total daily dose of the CBN may beselected from: at least 5 mg, at least 10 mg, at least 15 mg, at least20 mg, at least 25 mg, at least 30 mg, at least 35 mg, and at least 40mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, atleast 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85mg, at least 90 mg, and at least 95 mg.

The first pulse-release component (C₁) may be an immediate release (IR)formulation of the first cannabinoid API₁ and the second cannabinoidAPI₂, comprising the first portion (P₁) of the first cannabinoid API(API₁P₁) and a first portion (P₁) of the second cannabinoid API(API₂P₁). The first pulse-release component (C₁) may comprise one ormore binders, one or more disintegrants, one or more lubricants, one ormore flow aids, or any combinations thereof. The second pulse-releasecomponent (C₂) may be a delayed release (DR) formulation of the firstcannabinoid API₁ and the second cannabinoid API₂, comprising the secondportion (P₂) of the first cannabinoid API (API₁P₂) and a second portion(P₂) of the second cannabinoid API (API₂P₂). The second pulse-releasecomponent (C₂) may comprise one or more binders, one or more lubricants,one or more flow aids, or any combinations thereof. The secondpulse-release component may be coated with a first delayed-release layercomprising one or more pH-dependent and/or non-pH-dependent polymers,and optionally one or more plasticizers, one or more pore formers, oneor lubricants, or any combinations thereof. The third pulse-releasecomponent (C₃) may be a delayed release (DR) formulation of the firstcannabinoid API₁ and the second cannabinoid API₂, comprising the thirdportion (P₃) of the first cannabinoid API (API₁P₃) and a third portion(P₃) of the second cannabinoid API (API₂P₃). The third pulse-releasecomponent (C₃) may comprise one or more binders, one or more lubricants,one or more flow aids, or any combinations thereof. The thirdpulse-release component may be coated with a second delayed-releaselayer comprising one or more pH-dependent and/or non-pH-dependentpolymers, and optionally one or more plasticizers, one or more poreformers, one or lubricants, or any combinations thereof.

For each API, the first portion (P₁) may be independently selected from25% to 75% of the total daily dose, for each API, the second portion(P₂) may be independently selected from 25% to 75% of the total dailydose, and, for each API, the third portion (P₃) may be independentlyselected from 25% to 75% of the total daily dose.

In the first pulse-release component (C₁), the second pulse-releasecomponent (C₂), and/or the third pulse-release component (C₃), whenpresent: the binders may comprise from 1 to 60% (w/w), the disintegrantsmay comprise from 0.05 to 15% (w/w), the lubricants may comprise from0.5 to 5% (w/w), the flow aids may comprise from 0.05 to 0.5% (w/w), andthe pH-dependent and/or non-pH-dependent polymers may comprise from 0.5to 35% (w/w).

The first pulse-release component (C₁) may comprise from 2.5 mg to 30 mgof the first cannabinoid active pharmaceutical ingredient (API₁),wherein the API₁ is THC, and from 1.25 mg 30 to 75 mg of the secondcannabinoid active pharmaceutical ingredient (API₁), wherein the API₁ isCBN. The first pulse-release component (C₁) may comprisemicrocrystalline cellulose, hydroxypropylmethylcellulose, croscormellosesodium, magnesium stearate, or any combinations thereof. The secondpulse-release component (C₂) may comprise from 2.5 mg to 30 mg of thefirst cannabinoid active pharmaceutical ingredient (API₁), wherein theAPI₁ is THC, and from 1.25 mg to 75 mg of the second cannabinoid activepharmaceutical ingredient (API₁), wherein the API₁ is CBN. The secondpulse-release component (C₂) may comprise microcrystalline cellulose,cellulose acetate phthalate, magnesium stearate, or any combinationsthereof. The third pulse-release component (C₃) may comprise from 2.5 mgto 30 mg of the first cannabinoid active pharmaceutical ingredient(API₁), wherein the API₁ is THC, and from 1.25 mg to 75 mg of the secondcannabinoid active pharmaceutical ingredient (API₁), wherein the API₁ isCBN. The third pulse-release component (C₃) may comprisemicrocrystalline cellulose, methacrylic acid copolymer, magnesiumstearate, or any combinations thereof.

According to a third aspect, the present disclosure provides a method oftreating a sleep disorder in a subject in need thereof, the methodcomprising: administering to the subject an oral pulse-release dosageform described herein.

The method may include the following details, which can be combined withone another in any combinations unless clearly mutually exclusive:

The administering may result in an increase in the subject's totalsleeping time during the night.

The administering may result in an increase in the subject's total lightsleeping time during the night.

The administering may result in an increase in the subject's lightsleeping time as a proportion of total sleeping time during the night.

The administering may result in an increase in the subject's total timein bed during the night.

The increase may be measured using a SleepScore Max® system.

The administering may result in an increase in SleepScore number asdetermined using a SleepScore Max® system.

The administering may result in the subject experiencing an increase inone or more of: feeling well rested in the morning and/or during theday, perceived sleep quality, perceived total sleep time during thenight, or sleep satisfaction. Additionally or alternatively, the subjectmay experience a decrease in one or more of: perceived frequency ofawakenings during the night, number of times out of bed at night, numberof naps during the day, or perceived time awake at night.

The sleep disorder may comprise insomnia, wherein the insomnia isprimarily characterized by an inability to stay asleep during the night.

The insomnia may be characterized using a SleepScore Max® system.

Characterization of the sleep disorder may be reported by the subject.

The administering may not result in a decrease in latency to sleeponset, an alteration of time in deep sleep and/or REM sleep, a hangovereffect during the day after the administering, or any combinationsthereof.

The subject may have previously been administered with one or morecannabinoids for treating a medical condition.

The administering may be up to 30 minutes, 1 hour, or 2 hours before thesubject intends to begin sleeping at night.

BRIEF DESCRIPTION OF THE DRAWINGS

The present disclosure may be further understood through reference tothe attached figures in combination with the detailed description thatfollows.

FIG. 1 is a graph reporting an example in vitro dissolution release rate(g/mL per timepoint) of delta-9 Tetrahydrocannabinol (THC) versus timein hours of an example 2-pulse oral pharmaceutical composition tablet.

FIG. 2 is a graph reporting an example dissolution profile of cumulativerelease of % total THC dose versus time in hours of an example 2-pulseoral pharmaceutical composition tablet.

FIG. 3 is a schematic showing an example clinical study timeline.

FIG. 4 is a graph reporting example medical conditions for whichcannabis was used. Up to 3 conditions could be selected by eachparticipant.

FIG. 5 is a graph reporting example sleep concerns of clinical trialparticipants prior to using an example pulse-release dosage form of thepresent disclosure. Percentages do not total 100 because multipleanswers were allowed.

FIG. 6 is a graph reporting example forms of cannabis being used byclinical trial participants to help with sleep prior to the product useperiod. Percentages do not total 100 because multiple answers wereallowed.

FIG. 7 is a graph reporting example data on self-reported average numberof times participants woke up per night.

FIG. 8 is a graph reporting example self-reported average amount of timeper night spent awake after initially falling asleep.

FIG. 9 is a graph reporting example self-reported average number ofhours and minutes slept per night.

FIG. 10 is a graph reporting example self-reported number of morningsper week participants woke up feeling well rested.

FIG. 11 is a graph reporting example self-reported number of nights perweek participants felt satisfied with their sleep.

FIG. 12 is a graph reporting example self-reported number of days perweek participants napped.

FIG. 13 is a schematic showing an example clinical study timeline.

FIG. 14 is a graph reporting example medical conditions for whichcannabis was used. Up to 3 conditions could be selected by eachparticipant.

FIG. 15 is a graph reporting example sleep concerns of clinical trialparticipants prior to using an example pulse-release dosage form of thepresent disclosure. Percentages do not total 100 because multipleanswers were allowed.

FIG. 16 is a graph reporting example forms of cannabis being used byclinical trial participants to help with sleep prior to the product useperiod. Percentages do not total 100 because multiple answers wereallowed.

FIG. 17 is a graph reporting example data on self-reported averagenumber of days per week participants felt so sleepy/tired that itaffected them at school/work or in their private life. Note: * indicatessignificant at p<0.05 after 1 week of use. ** indicates significant atp<0.05 after 3 weeks of use.

FIG. 18 is a graph reporting example data on self-reported averagesleepiness of participants at bedtime. Note: ** indicates significant atp<0.05 after 3 weeks of use.

FIG. 19 is a graph reporting example data on self-reported averagenumber of nights per week participants reported falling asleep in theamount of time that they preferred. Note: ** indicates significant atp<0.05 after 3 weeks of use.

FIG. 20 is a graph reporting example data on self-reported averagenumber of minutes it took to fall asleep per night.

FIG. 21 is a graph reporting example data on self-reported averagenumber of mornings per week participants woke up feeling well rested.Note: ** indicates significant at p<0.05 after 3 weeks of use.

FIG. 22 is a graph reporting example data on self-reported averagenumber of nights per week participants felt satisfied with their sleep.Note: ** indicates significant at p<0.05 after 3 weeks of use.

DETAILED DESCRIPTION

Insomnia, defined as difficulty falling asleep or staying asleep, is themost common sleep disorder with approximately 30% of adults havingsymptoms each year (National Sleep Foundation. What is Insomnia?https://www.sleepfoundation.org/insomnia/what-insomnia, Accessed 2019;The American Academy of Sleep Medicine. Insomnia.https://aasm.org/resources/factsheets/insomnia.pdf, Accessed 2019). Itis a major contributing factor to motor vehicle deaths, and loss ofproductivity, due to insomnia, costs the US workforce $63.2 billionannually (The American Academy of Sleep Medicine. Insomnia.https://aasm.org/resources/factsheets/insomnia.pdf, Accessed 2019;Laugsand L E, Strand L B, Vatten L J, et. al. Insomnia Symptoms and Riskfor Unintentional Fatal Injuries—The HUNT Study. Sleep. 2014 Nov. 1;37(11):1777-86; Kessler R C, Berglund P A, Coulouvrat C, et al. Insomniaand the performance of US workers: results from the America insomniasurvey. Sleep. 2011 Sep. 1; 34(9):1161-71). A number of sleepmedications are available to improve sleep quality includingprescription drugs, over-the-counter medication and alternativetreatments. Of the alternative solutions available, cannabis hasreceived increased attention over the last two decades with thelegalization of medical cannabis in 33 states and Washington D.C.(National conference of state legislatures, State Medical MarijuanaLaws.http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx,Accessed 2019). According to recent studies, two-thirds of medicalcannabis users have reduced their sleep medication use since startingmedical cannabis, and they expect medical cannabis to improve theirsleep quality (Piper B J, DeKeuster R M, Beals M L, et al. Substitutionof medical cannabis for pharmaceutical agents for pain, anxiety andsleep. J Psychopharmacol. 2017 May; 31(5):569-575; Altman B R, Mian M N,Slavin M, Earleywine M. Cannabis Expectancies for Sleep. J PsychoactiveDrugs. 2019 Jul. 18:1-8). To date, the impact of cannabinoids on sleepis unclear.

Delta-9 Tetrahydrocannabinol (THC) is one of the most widely studiedcannabinoids on sleep, yet its effects are not well understood (Babson KA, Sottile J, Morabito D. Cannabis, Cannabinoids, and Sleep: A Review ofthe Literature. Curr Psychiatry Rep. 2017 April; 19(4):23; Gates P J,Albertella L, Copeland J. The effects of cannabinoid administration onsleep: a systematic review of human studies. Sleep Med Rev. 2014December; 18(6):477-87). Early studies focused on the connection betweenTHC and polysomnography. Cousens and DiMascio showed that THCsignificantly decreased time to fall asleep yet it causes a hangovereffect, defined as continued effects of a cannabinoid drug felt by thesubject during the following day (Cousens K, DiMascio A. (−) Delta 9 THCas a hypnotic. An experimental study of three dose levels.Psychopharmacologia. 1973 Dec. 20; 33(4):355-64). Conversely, Chaitreported that THC is not associated with a hangover effect (Chait L D.Subjective and behavioral effects of marijuana the morning aftersmoking. Psychopharmacology (Berl). 1990; 100(3):328-33). Otherpolysomnography studies suggested that THC reduces the duration of REMsleep and may increase the duration of Stage 4 sleep (Feinberg I, JonesR, Walker J M, et al. Effects of high dosagedelta-9-tetrahydrocannabinol on sleep patterns in man. Clin PharmacolTher. 1975 April; 17(4):458-66; Pivik R T, Zarcone V, Dement W C,Hollister L E. Delta-9- tetrahydrocannabinol and synhexl: effects onhuman sleep patterns. Clin Pharmacol Ther. 1972 May-June; 13(3):426-35).Recent studies focusing on self-reported sleep quality are alsoinconsistent. A few studies have shown that THC is sedative and reducessleep onset latency while many have found an association between THC andpoor sleep quality (Nicholson A N, Turner C, Stone B M, Robson P J.Effect of delta 9 THC and Cannabidiol on Nocturnal Sleep andEarly-morning Behavior in Young Adults. J Clin Psychopharmacol. 2004June; 24(3):305-13; Tringale R, Jensen C. Cannabis and insomnia.Depression. 2011; 4(12):0-68; Ogeil R P, Phillips J G, Rajaratnam S M,Broadbear J H. Risky drug use and effects on sleep quality and daytimesleepiness. Hum Psychopharmacol. 2015 September; 30(5):356-63).Ultimately, in previous studies, the optimal THC concentration, route ofadministration and administration time needed to positively impact sleepquality has not been determined (Watson N F, Badr M S, Belenky G, etal.; Consensus Conference Panel. Joint consensus statement of theAmerican Academy of Sleep Medicine and Sleep Research Society on therecommended amount of sleep for a healthy adult: methodology anddiscussion. Sleep. 2015 Aug. 1; 38(8):1161-83).

The present disclosure relates to oral cannabinoid pharmaceuticalcompositions and methods of treating sleep disorders using the oralcannabinoid pharmaceutical compositions.

A. Active Pharmaceutical Ingredients (API's)

In some embodiments, an API of the present disclosure can be acannabinoid. The term “cannabinoid” as used herein refers to severalclasses of compounds that can be found in plants of the genus Cannabis.There are at least 144 different cannabinoids that have been isolatedfrom cannabis, exhibiting varied effects. Synthetic encompass a varietyof distinct chemical classes: the classical cannabinoids structurallyrelated to THC, the nonclassical cannabinoids (cannabimimetics)including the aminoalkylindoles, 1,5-diarylpyrazoles, quinolines, andarylsulfonamides as well as eicosanoids related to endocannabinoids.

The classical cannabinoids are concentrated in a viscous resin ofcannabis plants produced in structures known as glandular trichomes. Themain classes of cannabinoids include, without limitation, THC(tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid), CBD(cannabidiol), CBDA (cannabidiolic acid), CBN (cannabinol), CBG(cannabigerol), CBC (cannabichromene), CBL (cannabicyclol), CBV(cannabivarin), THCC (tetrahydrocannabiorcol), THCV(tetrahydrocannabivarin), THCP (tetrahydrocannabiphorol), CBDV(cannabidivarin), CBCV (cannabichromevarin), CBGV (cannabigerovarin),CBGM (cannabigerol monomethyl ether), CBE (cannabielsoin), and CBT(cannabicitran). Cannabinoids of the present disclosure include, withoutlimitation: Cannabigerol-type (CBG) cannabinoids, such as Cannabigerolmonomethyl ether, Cannabinerolic acid A, Cannabigerovarin,Cannabigerolic acid A, Cannabigerolic acid A monomethyl ether, andCannabigerovarinic acid A; Cannabichromene-type (CBC) cannabinoids, suchas (±)-Cannabichromene, (±)-Cannabichromenic acid A,(±)-Cannabivarichromene, (±)-Cannabichromevarin, and(±)-Cannabichromevarinic acid A; Cannabidiol-type (CBD) cannabinoids,such as (−)-Cannabidiol, Cannabidiol momomethyl ether, Cannabidiol-C₄,(−)-Cannabidivarin, Cannabidiorcol, Cannabidiolic acid, andCannabidivarinic acid; Cannabinodiol-type (CBND) cannabinoids, such asCannabinodiol and Cannabinodivarin; Tetrahydrocannabinol-type (THC)cannabinoids, such as Δ⁹-Tetrahydrocannabinol,Δ⁹-Tetrahydrocannabinol-C₄, Δ⁹-Tetrahydrocannabivarin,Δ⁹-Tetrahydrocannabiorcol, Δ⁹-Tetrahydro-cannabinolic acid A,Δ⁹-Tetrahydro-cannabinolic acid B, Δ⁹-Tetrahydro-cannabinolic acid-C₄ Aand/or B, Δ⁹-Tetrahydro-cannabivarinic acid A,Δ⁹-Tetrahydro-cannabiorcolic acid A and/or B,(−)-Δ⁸-trans-(6aR,10aR)-Δ⁸-Tetrahydrocannabinol,(−)-Δ⁸-trans-(6aR,10aR)-Tetrahydrocannabinolic acid A, and(−)-(6aS,10aR)-Δ⁹-Tetrahydrocannabinol; Cannabinol-type (CBN)cannabinoids, such as Cannabinol, Cannabinol-C₄, Cannabivarin,Cannabinol-C₂, Cannabiorcol, Cannabinolic acid A, and Cannabinol methylether; Cannabitriol-type (CBT) cannabinoids, such as(−)-(9R,10R)-trans-Cannabitriol, (+)-(9S,10S)-Cannabitriol,(±)-(9R,10S/9S,10R)-Cannabitriol,(−)-(9R,10R)-trans-10-O-Ethyl-cannabitriol,(±)-(9R,10R/9S,10S)-Cannabitriol-C₃,8,9-Dihydroxy-Δ^(6a(10a))-tetrahydrocannabinol, Cannabidiolic acid Acannabitriol ester,(−)-(6aR,9S,10S,10aR)-9,10-Dihydroxy-hexahydrocannabinol, Cannabiripsol,(−)-6a,7,10a-Trihydroxy-Δ⁹-tetrahydrocannabinol,10-Oxo-^(Δ6a(10a))-tetrahydrocannabinol; Cannabielsoin-type (CBE)cannabinoids such as (5aS,6S,9R,9aR)-Cannabielsoin,(5aS,6S,9R,9aR)-C₃-Cannabielsoin, (5aS,6S,9R,9aR)-Cannabielsoic acid A,(5aS,6S,9R,9aR)-Cannabielsoic acid B, (5aS,6S,9R,9aR)-C₃-Cannabielsoicacid B, Cannabiglendol-C₃, Dehydrocannabifuran, and Cannabifuran;Isocannabinoids such as (−)-Δ⁷-trans-(1R,3R,6R)-Isotetrahydrocannabinol,(±)-Δ⁷-1,2-cis-(1R,3R,6S/1S,3S,6R)-Isotetrahydro-cannabivarin, and(−)-Δ⁷-trans-(1R,3R,6R)-Isotetrahydrocannabivarin; Cannabicyclol-type(CBL) cannabinoids such as (±)-(1aS,3aR,8bR,8cR)-Cannabicyclol,(±)-(1aS,3aR,8bR,8cR)-Cannabicyclolic acid A, and(±)-(1aS,3aR,8bR,8cR)-Cannabicyclovarin; Cannabicitran-type (CBT)cannabinoids such as Cannabicitran; and Cannabichromanone-type (CBCN)cannabinoids such as Cannabichromanone, Cannabichromanone-C₃, andCannabicoumaronone.

In some embodiments, the term “cannabinoid” as used herein refers tocompounds that may be extracted from, and/or derived from Cannabisplants using methods known in the art. For example, cannabinoids can beseparated from the cannabis plant by extraction with organic solvents orusing supercritical solvent extraction with carbon dioxide. Cannabinoidsmay be obtained in oils extracted from cannabis plants, and thereafterfurther isolated, purified, and converted into derivatives. In someembodiments, the term “cannabinoid” as used herein may also refer tosuch compounds that may be produced synthetically or using recombinantbiotechnology methods, as may be identified by persons of ordinary skillin the art.

Cannabinoids of the present disclosure may include stereoisomersthereof, and modified forms thereof, such as a pharmaceuticallyacceptable salt, ester, derivative, analog, prodrug, hydrate, or solvatethereof.

In some embodiments, a pharmaceutical compositions of the presentdisclosure can include, without limitation, one or more cannabinoids,two or more cannabinoids, or three or more cannabinoids. In someembodiments, the cannabinoid may be THC, CBN, CBD, or any combinationsthereof.

The best studied cannabinoids include tetrahydrocannabinol (THC),cannabidiol (CBD) and cannabinol (CBN). Δ⁹- tetrahydrocannabinol (Δ⁹-THCor THC), is also known by its International Non-Proprietary Name (INN)as dronabinol. The unsaturated bond in the cyclohexene ring is locatedbetween C-9 and C-10 in the more common dibenzopyran ring numberingsystem. There are four stereoisomers of THC, but only the (−)-transisomer occurs naturally (CAS-1972-08-03). The fully systematic name forthis THC isomer is(−)-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol.Two related substances, Δ⁹- tetrahydrocannabinol-2-oic acid andΔ⁹-tetrahydrocannabinol-4-oic acid (THCA), are also present in cannabis,sometimes in large amounts. During smoking, THCA is partly converted toTHC. The active isomer Δ⁸-THC, in which the unsaturated bond in thecyclohexene ring is located between C-8 and C-9, is found in muchsmaller amounts. Other closely related substances that occur in cannabisinclude cannabidiol (CBD) and, in aged samples, cannabinol (CBN), bothof which have quite different pharmacological effects to THC.

THC is the most known active component of cannabis. The pharmacology ofcannabis is complicated by the presence of a wide range of cannabinoids.At small doses, cannabis produces euphoria, relief of anxiety, sedationand drowsiness. In some respects, the effects are similar to thosecaused by alcohol. Anandamide has been identified as the endogenousligand for the cannabinoid receptor and has pharmacological propertiessimilar to those of THC. When cannabis is smoked, THC can be detected inplasma within seconds of inhalation; it has a half-life of 2 hours.Following smoking of the equivalent of 10-15 mg over a period of 5-7minutes, peak plasma levels of Δ⁹-THC are around 100 μg/L. It is highlylipophilic and widely distributed in the body. Two active metabolitesare formed: 11-hydroxy-Δ⁹-THC and 8β-hydroxy-Δ⁹-THC. The first isfurther metabolized to Δ⁹-THC-11-oic acid. Two inactive substances arealso formed—8α-hydroxy-Δ⁹-THC and 8α,11-dihydroxy-Δ⁹-THC and many otherminor metabolites, most of which appear in the urine and feces asglucuronide conjugates. Some metabolites can be detected in the urinefor up to 2 weeks following smoking or ingestion.

Bioavailability following the smoking route was reported as 2-56%, duein part to intra- and inter-subject variability in smoking dynamics,which contributes to uncertainty in dose delivery. The number, duration,and spacing of puffs, hold time, and inhalation volume, or smokingtopography, greatly influences the degree of drug exposure (Huestis M.,“Human Cannabinoid Pharmacokinetics” Chem Biodivers. 2007 August; 4(8):1770-1804).

The chemical structure of Δ⁹-THC may be represented as Formula I:

The chemical structure of CBN may be represented as Formula II:

At least six CBN-type cannabinoids are known. With ring A aromatized,they may be formed as oxidation artifacts of THC and CBD, respectively.Their concentration in cannabis products may depend on age and storageconditions. CBN has been shown to induce drowsiness, and reduced time tosleep, but has been shown to create “hangover” symptoms when used alonefor sleep.

THC and CBN are known to be readily absorbed via the inhalation route,but very little is known about the biotransformation of CBN followingoral administration and release in the gastrointestinal tract.Furthermore, to date, very little, if any, published information isavailable regarding the extent, or components of, biotransformation ofcannabinoids, such as THC or CBN, following a delayed-release e.g. intothe duodenum.

The pharmaceutical formulations described herein are provided to meetthe need in the art for oral dosage forms that provide controlledrelease into the gastrointestinal tract of a subject, in order toprovide delivery of cannabinoid APIs described herein that in someembodiments may be useful for treating sleep disorders.

B. Pharmaceutical Formulations

In some embodiments, the present disclosure provides oral pulse-releasecompositions and dosage forms thereof, comprising a dose, e.g. a totaldaily dose, of one or more cannabinoid active pharmaceuticalingredients.

The terms “pulse-release” or “pulsatile” formulation, as used hereinrefers in general to release of a portion of a total API dose, e.g. aportion of a total daily API dose, in a burst, followed by periods oflittle or no release (e.g., lag phase) in a defined temporal pattern. Inparticular, oral pulsatile drug release pertains to the burst deliveryof drugs following a temporal pattern from the time of oraladministration. In some embodiments, the pulse-release formulations ofthe present disclosure may combine a range of formulation approaches,including single- or multiple-unit immediate-release, delayed-release,and/or extended-release components. For example, in some embodiments,the delayed release components in the pulsatile formulations describedherein may be configured to release an API at a desired site within thegastrointestinal tract, and/or release of the API after a defined timeperiod. In some embodiments, an oral pulse-release dosage form of thepresent disclosure may comprise one or more immediate release oralpharmaceutical formulation components, one or more delayed release oralpharmaceutical formulation components, one or more extended release oralpharmaceutical formulation components, or any combinations thereof.

In some embodiments, when administered orally to a subject, an oralpulse-release dosage form of the present disclosure is configured toprovide release of a dosage, e.g. a daily dosage, of the one or morecannabinoids into the gastrointestinal tract of the subject, dividedinto at least 2 separate releases, or pulses separated by at least 2hours, and not more than 6 hours, between releases. In some embodiments,when administered orally to a subject, an oral pulse-release dosage formof the present disclosure is configured to provide release of a dosage,e.g. a daily dosage, of the one or more cannabinoids into thegastrointestinal tract of the subject, divided into at least 3 separatereleases, or pulses separated by at least 1 hours, and not more than 4hours, between releases.

In some embodiments, an oral pulse-release dosage form of the presentdisclosure may provide a total daily dose of a cannabinoid API, or apartial daily dose of a cannabinoid API. In some embodiment, aplurality, e.g. 2, 3, or more of the oral pulse-release dosage form ofthe present disclosure may be administered to a subject to provide atotal daily dose. In some embodiments, the oral pulse-release dosageform of the present disclosure may be administered once, twice, threetimes or more, per day to provide a total daily dose of a cannabinoidAPI.

In some embodiments, the pulse-release dosage forms of the presentdisclosure are configured to release a portion of an API in the gastricregion (e.g. in the stomach), and the remaining portion in the smallintestine e.g. distal duodenum, or other distal sites in thegastrointestinal tract.

Accordingly, in some embodiments, the present disclosure provides anoral pulse-release dosage form, comprising a total dose, e.g. a totaldaily dose, of a cannabinoid active pharmaceutical ingredient (API),wherein the pulse-release dosage form comprises a first pulse-releasecomponent (C₁) comprising a first portion (P₁) of the cannabinoid API(API-P₁), and at least a second pulse-release component (C₂) comprisinga second portion (P₂) of the first cannabinoid API (API₁P₂). In the oralpulse-release dosage form, the total dose, e.g. total daily dose, of theAPI is divided between the first portion (P₁) in the first pulse-releasecomponent (C₁) and at least the second portion (P₂) in the at leastsecond pulse-release component (C₂). When the pulse-release dosage formis placed in a simulated gastrointestinal environment, the pulse-releasedosage form provides release of the API-P₂ beginning from 2 to 6 hoursafter release of the API-P₁ begins.

The term “simulated gastrointestinal environment” is intended to be usedherein to convey its ordinary meaning as understood in the art, and isunderstood in a broad sense to mean conditions that mimic oraladministration, for example, an aqueous environment of low pH, 1-5 forexample, followed after a period of up to about 2 hours with immersionin a higher pH aqueous environment, such as pH 6.8, for example, or a 3stage environment in which the low pH is followed by an intermediate pHof about 6 wherein the environments are maintained at about 37.0° C.Alternatively, for certain embodiments a simulated gastrointestinalenvironment is described as the USP Apparatus I (Baskets) with agitationin which the composition is placed in 700 ml aqueous solution of 0.1NHCl pH 1.1, for up to 2 hours followed by 2-8 hours in sodium phosphatebuffer at pH 6.0; followed by 6-20 hours in sodium phosphate buffer, pH7.2, adding NaOH to adjust pH to 7.2. In some embodiments, thedissolution testing can include placing a dosage form in an aqueoussolution of 0.1N HCl pH 1.1 for 2 hours followed by 8 hours in sodiumphosphate buffer at pH 6.8, at 37° C.±0.5° C., and sampling atappropriate time intervals, e.g. at 1, 1.5, 2, 3, 3.5, 4, 5, 6, 7, 8, 9and 10 hours.

For example, a two-stage dissolution test is described in USP GeneralChapter <711>Dissolution, in which the integrity of an enteric coatingis determined in an acidic environment and the drug release is measuredin a neutral environment. The test can be performed using eithermedium-addition or medium exchange methods; both may start with an acidstage in 0.1 N hydrochloric acid for two hours and follow with a bufferstage in phosphate buffer at pH 6.8 for e.g. 45 min or a specific timeas needed for the individual drug product. Medium addition or mediumexchange procedures may be used. For the medium-addition approach, adesignated amount of concentrated phosphate buffer may be added to thedissolution vessel to neutralize the medium to the target pH before thebuffer stage starts. The operations of adding the buffer and adjustingthe pH may be completed within 5 min. For the medium-exchange approach,the acid medium may be drained after two hours, and a full amount of pH6.8 buffer may be added to the same vessel for the buffer stage. Thedosage unit is typically left undisturbed during the medium change.Alternatively, the vessel containing the acid can be removed andreplaced with another vessel containing the buffer, and the dosage unittransferred to the new vessel.

Parameters of suitable API-specific biorelevant dissolution methods suchas in vitro dissolution analysis can be determined by skilled personswithout undue experimentation upon reading the present disclosure. Forexample, and without limitation, an in-vitro non-sink, gastric transferdissolution method may be used to analyze the release and dissolution ofAPI.

At pre-determined time points, samples may be drawn from the dissolutionvessel and centrifuged using an ultracentrifuge. The supernatants may befurther diluted using an HPLC diluent and analyzed by a suitable HPLCmethod. Parameters such as peak release rate (PRR) and the area underdrug dissolution curve (AUDC), among others, may be calculated, e.g. bythe linear trapezoidal method.

Each of the pulse-release components that may be combined to provide theoral pulse-release dosage form may be analyzed separately by in vitrodissolution tests, to determine the pulse-release timing for eachpulse-release component of the oral pulse-release dosage form. The“beginning” of release from a pulse-release component may be defined asthe time at which a detectable amount of the API is present in thedissolution media, or when a certain percentage of the total dose isdetected in the dissolution media, e.g. at least 1%, 5%, or 10% of thetotal amount of the API present in the particular pulse-releasecomponent.

For example, in some embodiments, the simulated gastrointestinalenvironment may be an aqueous solution of 0.1N HCl pH 1.1 for 2 hoursfollowed by 8 hours in sodium phosphate buffer at pH6.8, at 37° C.±0.5°C.

In some embodiments, when the pulse-release dosage form is placed in asimulated gastrointestinal environment, the pulse-release dosage formmay provide a second time of peak release rate (PRR₂) of the API fromabout 2 to 6 hours after a first time of peak release rate (PRR₁). Forexample, FIG. 1 and Example 3 describe example in vitro dissolution dataof an example pulse-release dosage form of the present disclosure. Insome embodiments, when the pulse-release dosage form is placed in asimulated gastrointestinal environment, a first time of PRR of the APImay be after 1-2 hours, and a second time of PRR may be from about 2 to6 hours after the first time of PRR.

In some embodiments, the pulse-release dosage form may comprise a totaldose, e.g. a total daily dose, of a cannabinoid API from 1 mg to 100 mg,for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69,70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87,88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg.

In some embodiments, the first pulse-release component (C₁) may be animmediate release (IR) formulation of the cannabinoid API. For example,an IR formulation of the API may include, without limitation, the firstportion (P₁) of the cannabinoid API (API-P₁), as well as one or morebinders, one or more disintegrants, one or more lubricants, one or moreflow aids, or any combinations thereof. In some embodiments, the secondpulse-release component (C₂) may be a delayed release (DR) formulationof the cannabinoid API. For example, a DR formulation of the API mayinclude, without limitation, the second portion (P₂) of the cannabinoidAPI (API-P₂), as well as one or more binders, one or more lubricants,one or more flow aids, or any combinations thereof, and the secondpulse-release component may be coated with a layer of one or morepH-dependent or non-pH-dependent polymers, one or more plasticizers, orboth.

In some embodiments, the binder may include, but is not limited to,microcrystalline cellulose, corn starch, pregelatinized starch, potatostarch, rice starch, sodium carboxymethyl starch,hydroxypropylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose, ethylcellulose, chitosan, hydroxychitosan,hydroxymethylatedchitosan, cross-linked chitosan, cross-linkedhydroxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose,maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone(PVP), acrylic acid derivatives (Carbopol, Eudragit, etc.), polyethyleneglycols, such a low molecular weight PEGs (PEG2000-10000) and highmolecular weight PEGs (Polyox) with molecular weights above 20,000daltons.

In some embodiments, the binders may be present in a pulse-releasecomponent of the pulse-release dosage form in the range of 1.0 to 60%(W/W).

In addition, other ingredients that may be included in a pulse-releasecomponent of the pulse-release dosage form to aid in the dissolution ofthe API, or the breakdown of the pulse-release component after ingestionor administration may include, without limitation, one or moresurfactants, such as sodium lauryl sulfate, sodium monoglycerate,sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitanmonooleate, glyceryl monostearate, glyceryl monooleate, glycerylmonobutyrate, a non-ionic surfactant such as the Pluronic line ofsurfactants, or any other material with surface active properties.

In some embodiments, the disintegrant may include, but is not limitedto, sodium starch glycolate, corn starch, rice starch, gar gum,polyvinylpolypyrrolidone, croscarmellose, andhydroxypropylmethylcellulose, among others.

In some embodiments, the disintegrants may be present in a pulse-releasecomponent of the pulse-release dosage form in the range of 0.05-15%(W/W).

In some embodiments, the lubricant may include, but is not limited to,magnesium stearate, calcium stearate, and stearic acid, among others.

In some embodiments, the lubricants may be present in a pulse-releasecomponent of the pulse-release dosage form in the range of 0.05-5%(W/W).

In some embodiments, the flow aid may include, but is not limited to,colloidal silicone dioxide, and magnesium stearate, among others.

In some embodiments, the flow aids may be present in a pulse-releasecomponent of the pulse-release dosage form in the range of 0.05-0.5%(W/W).

In some embodiments, the polymer coating may include, but is not limitedto, one or more pH-dependent or non-pH-dependent excipients. Examples ofnon-pH dependent polymers include ethyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,carboxymethyl cellulose, copolymer of ethyl acrylate, methylmethacrylate (e.g., Eudragit R S), among others. Examples ofpH-dependent excipients include methacrylic acid copolymers,hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethylcellulose phthalate, and cellulose acetate phthalate, among others. ThepH-dependent polymer coating may also include a pore former, such aspovidone, polyethylene glycol, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, among others, sugars such as sucrose,mannitol, lactose, and salts, such as sodium chloride, sodium citrate,among others. In some embodiments, the polymer coating may include aplasticizer, such as acetylated citrated esters, acetylated glycerides,castor oil, citrate esters, dibutylsebacate, glyceryl monostearate,diethyl phthalate, glycerol, medium chain triglycerides, propyleneglycol, and polyethylene glycol. The coating may also include one ormore additional excipients, such as lubricants (e.g., magnesiumstearate, talc among others). The coating can be applied usingconventional coating techniques such as fluidized bed coating, pancoating, among others.

In certain embodiments, the pH-dependent polymer can be apharmaceutically acceptable acrylic polymer, including but not limitedto, acrylic acid and methacrylic acid copolymers, methyl methacrylate,methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly (methacrylic acid), methacrylic acid alkylamine copolymerpoly(methyl methacrylate), poly(methacrylic acid)(anhy-dride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. In certain other embodiments, theacrylic polymer is comprised of one or more ammonia methacrylatecopolymers. Ammonio methacrylate copolymers are well known in the art,and are described as fully polymerized copolymers of acrylic andmethacrylic acid esters with a low content of quaternary ammoniumgroups. In still other embodiments, the acrylic polymer may be anacrylic resin lacquer such as a Eudragit®. In further embodiments, theacrylic polymer comprises a mixture of two acrylic resin lacquerscommercially available from Evonik/Rohm Pharma under the trade namesEudragit® RL30D and Eudragit® RS30D, respectively. Eudragit® RL30D andEudragit® RS30D are copolymers of acrylic and methacrylic esters with alow content of quaternary ammonium groups, the molar ratio of ammoniumgroups to the remaining neutral (meth)acrylic esters being 1:20 inEudragit® RL30D and 1:40 in Eudragit® RS30D. Eudragit® S-100 andEudragit® L-100 are also suitable for use herein. The code designationsRL (high permeability) and RS (low permeability) refer to thepermeability properties of these agents. Eudragit® mixtures areinsoluble in water and in digestive fluids. However, multi-particulatesystems formed to include the same are swellable and permeable inaqueous solutions and digestive fluids. The polymers described abovesuch as Eudragit® RL/RS may be mixed together in any desired ratio inorder to ultimately obtain an extended release formulation having adesirable dissolution profile. One skilled in the art will recognizethat other acrylic polymers may also be used, such as, for example,Eudragit® L.

In some embodiments, the polymer coatings may be present in apulse-release component of the pulse-release dosage form in the range of0.5-35% (W/W).

In some embodiments, the pulse-release dosage form may include APIcoated cores. In some embodiments, the cores may comprise non-pareils orsugar spheres.

In some embodiments, the pulse-release dosage form may optionallycomprise a seal coat. In some embodiments, a DR pulse-release componentof the pulse-release dosage form may be coated with a polymer coating byfluidized bed coating.

In some embodiments, a pulse-release component of the present disclosurecan be prepared by any suitable method known in the art, such as mixingthe ingredients in a suitable pharmaceutical mixer or granulator such asa planetary mixer, high-shear granulator, fluid bed granulator, orextruder, in the presence of water or other solvent, or in a hot meltprocess. If water or other solvent is used, the blend may be dried in asuitable pharmaceutical drier, such as a vacuum oven or forced-air oven.After allowing the product to cool, the product may be sieved orgranulated, and compressed using a suitable tablet press, such as arotary tablet press.

A pharmaceutical formulation of the present disclosure may be furtherprocessed into a solid dosage form suitable for oral administration,such as a pill, tablet or capsule. In some embodiments, thepharmaceutical formulation of the present disclosure may be provided inoral dosage forms such as a syrup, film, orally-disintegrating tablet, aliquid solution or suspension (e.g., drink or syrup), a powder, orliquid or solid crystals, or a paste.

An example method of formulating an example pulse-release oral dosageform of the present disclosure is described in Example 2.

In some embodiments, in the oral pulse-release dosage form of thepresent disclosure, where the dosage, e.g. the daily dosage, of the APIis divided into at least 2 separate releases, the percentage of APIreleased from the first portion (P₁) may be from 25% to 75% of the totaldose, e.g. the total daily dose, and the percentage of API released fromthe second portion (P₂) may be from 25% to 75% of the total dose, e.g.the total daily dose.

In certain embodiments, the cannabinoid API may be THC. In certainembodiments, the cannabinoid API may be CBN.

In some embodiments, in the oral pulse-release dosage form, the firstpulse-release component (C₁) may include from at least 2.5 mg to atleast 30 mg THC. In some embodiments, in the oral pulse-release dosageform, the first pulse-release component (C₁) may include from at least1.25 mg to at least 75 mg CBN. In some embodiments, in the oralpulse-release dosage form, the second pulse-release component (C₂) mayinclude from at least 2.5 mg to at least 30 mg THC. In some embodiments,in the oral pulse-release dosage form, the second pulse-releasecomponent (C₂) may include from at least 1.25 mg to at least 75 mg CBN.

In some embodiments, the oral pulse-release dosage form of the presentdisclosure may include a first cannabinoid API and a second cannabinoidAPI. Accordingly, in some embodiments, the oral pulse-release dosageform may include a total dose, e.g. a total daily dose of a firstcannabinoid active pharmaceutical ingredient (API₁) and a total dose e.ga total daily dose of a second cannabinoid API (API₂), wherein thepulse-release dosage form comprises: a first pulse-release component(C₁) comprising a first portion (P₁) of the first cannabinoid API(API₁P₁) and a first portion (P₁) of the second cannabinoid API(API₂P₁); and at least a second pulse-release component (C₂) comprisinga second portion (P₂) of the first cannabinoid API (API₁P₂) and a secondportion (P₂) of the second cannabinoid API (API₂P₂). In the oralpulse-release dosage form, the total dose e.g the total daily dose ofeach of the API₁ and the API₂ is divided between the first portion (P₁)in the first pulse-release component (C₁) and at least the secondportion (P₂) in the at least second pulse-release component (C₂). Whenthe pulse-release dosage form is placed in a simulated gastrointestinalenvironment, e.g. an aqueous solution of 0.1N HCl pH 1.1 for 2 hoursfollowed by 8 hours in sodium phosphate buffer at pH 6.8, at 37° C.±0.5°C., the pulse-release dosage form provides release of the API₁P₂ and theAPI₂P₂ beginning from 2 to 6 hours after release of the API₁P₁ and theAPI₂P₁ begins.

In some embodiments, when the pulse-release dosage form is placed in asimulated gastrointestinal environment, the pulse-release dosage formmay provide a second time of peak release rate (PRR₂) of each of theAPI₁ (PRR₂API₁) and the API₂ (PRR₂API₂) from about 2 to 6 hours after afirst time of peak release rate (PRR₁). In some embodiments, the PRR₁may be after 1-2 hours.

In some embodiments, the first cannabinoid API₁ may be THC and thesecond cannabinoid API₂ may be cannabinol (CBN), and the total dose,e.g. the total daily dose, of the THC is from 1 mg to 40 mg and thetotal dose, e.g. the total daily dose of the CBN is from 2.5 mg to 100mg.

In some embodiments, the first cannabinoid API₁ may be THC and thesecond cannabinoid API₂ may be CBN, and the total dose, e.g. the totaldaily dose, of the THC is selected from: at least 1 mg, at least 2 mg,at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 8mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, atleast 30 mg, and at least 35 mg, and the total dose e.g. the total dailydose, of the CBN is selected from: at least 2.5 mg, at least 3 mg, atleast 4 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20mg, at least 25 mg, at least 30 mg, at least 35 mg, and at least 40 mg,at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg,at least 90 mg, and at least 95 mg.

In some embodiments, the first pulse-release component (C₁) may be animmediate release (IR) formulation of the first cannabinoid API₁ and thesecond cannabinoid API₂, comprising the first portion (P₁) of the firstcannabinoid API (API₁P₁) and the first portion (P₁) of the secondcannabinoid API (API₂P₁). In some embodiments, the second pulse-releasecomponent (C₂) may be a delayed release (DR) formulation of the firstcannabinoid API₁ and the second cannabinoid API₂, comprising the secondportion (P₂) of the first cannabinoid API (API₁P₂) and a second portion(P₂) of the second cannabinoid API (API₂P₂).

In some embodiments, for each API, the first portion (P₁) may beindependently selected from 25% to 75% of the total dose, e.g. the totaldaily dose, and for each API the second portion (P₂) may beindependently selected from 25% to 75% of the total dose, e.g. the totaldaily dose.

In some embodiments, the first pulse-release component (C₁) may comprisefrom 0.5 mg to 30 mg of the first cannabinoid active pharmaceuticalingredient (API₁), wherein the API₁ is THC, and from 1.25 mg to 75 mg ofthe second cannabinoid active pharmaceutical ingredient (API₁), whereinthe API₁ is CBN. The second pulse-release component (C₂) may comprisefrom 0.5 mg to 30 mg of the first cannabinoid active pharmaceuticalingredient (API₁), wherein the API₁ is THC, and from 1.25 mg to 75 mg ofthe second cannabinoid active pharmaceutical ingredient (API₁), whereinthe API₁ is CBN.

In some embodiments, the daily dosage is at least 1 mg THC and at least10 mg CBN. In some embodiments, the daily dosage is at least 2 mg THCand at least 20 mg CBN. In some embodiments, the daily dosage is atleast 4 mg THC and at least 40 mg CBN. In some embodiments, the dailydosage is at least 5 mg THC and at least 2.5 mg CBN. In someembodiments, the daily dosage is at least 6 mg THC and at least 3 mgCBN. In some embodiments, the daily dosage is at least 8 mg THC and atleast 4 mg CBN. In some embodiments, the daily dosage is at least 5 mgTHC and at least 10 mg CBN. In some embodiments, the daily dosage is atleast 10 mg THC and at least 10 mg CBN. In some embodiments, the dailydosage is at least 20 mg THC and at least 10 mg CBN. In someembodiments, the daily dosage is at least 20 mg THC and at least 20 mgCBN. In some embodiments, the daily dosage is at least 10 mg THC and atleast 20 mg CBN. In some embodiments, the daily dosage is at least 10 mgTHC and at least 25 mg CBN. In some embodiments, the daily dosage is atleast 10 mg THC and at least 30 mg CBN. In some embodiments, the dailydosage is at least 10 mg THC and at least 40 mg CBN.

Example formulations of the pulse-release oral dosage forms of thepresent disclosure are provided in Example 1.

In some embodiments, the oral pulse-release dosage form comprises atotal dose e.g. a total daily dose of a first cannabinoid activepharmaceutical ingredient (API₁) and a total dose e.g. a total dailydose of a second cannabinoid API (API₂), wherein the pulse-releasedosage form comprises a first pulse-release component (C₁) comprising afirst portion (P₁) of the first cannabinoid API (API₁P₁) and a firstportion (P₁) of the second cannabinoid API (API₂P₁), a secondpulse-release component (C₂) comprising a second portion (P₂) of thefirst cannabinoid API (API₁P₂) and a second portion (P₂) of the secondcannabinoid API (API₂P₂), and at least a third pulse-release component(C₃) comprising a third portion (P₃) of the first cannabinoid API(API₁P₃) and a third portion (P₃) of the second cannabinoid API(API₂P₂). In the oral pulse-release dosage form, the total dose e.g. thetotal daily dose of each of the API₁ and the API₂ is divided between thefirst portion (P₁) in the first pulse-release component (C₁), the secondportion (P₂) in the second pulse-release component (C₂), and at leastthe third portion (P₃) in the at least third pulse-release component(C₃). When the pulse-release dosage form is placed in an aqueoussolution of 0.1N HCl pH 1.1 for 2 hours followed by 8 hours in sodiumphosphate buffer at pH 6.8, at 37° C.±0.5° C., the pulse-release dosageform provides release of the API₁P₂ and the API₂P₂ beginning from 1 to 4hours after release of the API₁P₁ and the API₂P₁ begins, and release ofthe API₁P₃ and the API₂P₃ beginning from 1 to 4 hours after release ofthe API₁P₂ and the API₂P₂ begins.

In some embodiments, the oral pulse-release dosage form provides asecond time of peak release rate (PRR₂) of each of the API₁ (PRR₂API₁)and the API₂ (PRR₂API₂) from about 1 to 4 hours after a first time ofpeak release rate (PRR₁) and a third time of peak release rate (PRR₃) ofeach of the API₁ (PRR₃API₁) and the API₂ (PRR₃API₂) from about 1 to 4hours after the second time of peak release rate (PRR₂). In someembodiments, the PRR₁ is after 1-2 hours.

In some embodiments, when the oral pulse-release dosage form providesrelease of a dosage, e.g. a daily dosage, of the API₁ and the API₂ intothe gastrointestinal tract of the subject, divided into at least 3separate releases, the first cannabinoid API₁ may be THC and the secondcannabinoid API₂ may be CBN. The total dose, e.g. the total daily dose,of the THC may be from 10 mg to 40 mg and the total dose e.g. the totaldaily dose of the CBN may be from 5 mg to 100 mg. In some embodiments,the first cannabinoid API₁ is THC and the second cannabinoid API₂ isCBN, and the total dose e.g. the total daily dose of the THC is selectedfrom: at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, atleast 30 mg, and at least 35 mg, and the total dose e.g. the total dailydose of the CBN is selected from: at least 5 mg, at least 10 mg, atleast 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, atleast 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80mg, at least 85 mg, at least 90 mg, and at least 95 mg.

In some embodiments, the first pulse-release component (C₁) may be animmediate release (IR) formulation of the first cannabinoid API₁ and thesecond cannabinoid API₂, comprising the first portion (P₁) of the firstcannabinoid API (API₁P₁) and a first portion (P₁) of the secondcannabinoid API (API₂P₁). The second pulse-release component (C₂) may bea delayed release (DR) formulation of the first cannabinoid API₁ and thesecond cannabinoid API₂, comprising the second portion (P₂) of the firstcannabinoid API (API₁P₂) and a second portion (P₂) of the secondcannabinoid API (API₂P₂). The third pulse-release component (C₃) may bea delayed release (DR) formulation of the first cannabinoid API₁ and thesecond cannabinoid API₂, comprising the third portion (P₃) of the firstcannabinoid API (API₁P₃) and a third portion (P₃) of the secondcannabinoid API (API₂P₃). The second pulse-release component may becoated with a first delayed-release layer comprising one or morepH-dependent and/or non-pH-dependent polymers, and optionally one ormore plasticizers, one or more pore formers, and/or one or lubricants.The third pulse-release component may be coated with a seconddelayed-release layer comprising one or more pH-dependent and/ornon-pH-dependent polymers, and optionally one or more plasticizers, oneor more pore formers, and/or one or lubricants. The seconddelayed-release layer may provide a delayed release of 1-4 hours longerthan the first delayed-release layer.

In some embodiments, for each API, the first portion (P₁) may beindependently selected from 25% to 75% of the total dose e.g. the totaldaily dose, for each API, the second portion (P₂) may be independentlyselected from 25% to 75% of the total dose e.g. the total daily dose,and, for each API, the third portion (P₃) may be independently selectedfrom 25% to 75% of the total dose e.g. the total daily dose.

In some embodiments, the first pulse-release component (C₁) may includefrom 2.5 mg to 30 mg of the first cannabinoid active pharmaceuticalingredient (API₁), wherein the API₁ is THC, and from at least 1.25 mg to75 mg of the second cannabinoid active pharmaceutical ingredient (API₁),wherein the API₁ is CBN. The second pulse-release component (C₂) mayinclude from 2.5 mg to 30 mg of the first cannabinoid activepharmaceutical ingredient (API₁), wherein the API₁ is THC, and from 1.25mg to 75 mg of the second cannabinoid active pharmaceutical ingredient(API₁), wherein the API₁ is CBN. The third pulse-release component (C₃)may include from 2.5 mg to 30 mg of the first cannabinoid activepharmaceutical ingredient (API₁), wherein the API₁ is THC, and from 1.25mg to 75 mg of the second cannabinoid active pharmaceutical ingredient(API₁), wherein the API₁ is CBN.

C. Method of Treating a Sleep Disorder

In some embodiments, the present disclosure provides a method oftreating a sleep disorder in a subject in need thereof, the methodcomprising administering to the subject an oral pulse-release dosageform of the present disclosure. In some embodiments, the administeringmay be up to 30 minutes, up to 1 hour, or up to 2 hours before thesubject intends to begin sleeping at night.

The description herein is primarily directed to treatment of sleepdisorders in subjects with a typical schedule, wherein the subjectintends to go to sleep starting from around 9 P.M. to about midnight,for example. Accordingly, terms used herein such as “at night”, “duringthe night” and so on are intended to refer to the usual period of timewhen the subject intends to be asleep, and, similarly, terms such as “inthe morning” are intended to refer to a period after the subject's usualsleeping time. It is understood, however, that the use and efficacy ofthe compositions and methods described herein, is not limited to such aschedule, but can be adopted for use with different daily schedules,such as night workers, or people with more variable sleep patterns.

In some embodiments, the term sleep disorder as used herein moreparticularly refers to insomnia. Insomnia may include a difficultyfalling asleep or staying asleep, or both. In some embodiments, thesleep disorder may be characterized primarily or predominantly byvarious symptoms, such as difficulty falling asleep or may becharacterized primarily or predominantly by difficulty staying asleep,either in an individual subject, or in a group of subjects, such as apopulation of subjects. In some embodiments, the sleep disorder mayinclude, without limitation, one or more of insufficient total sleepingtime during the night, increased frequency of awakenings during thenight, increased number of times out of bed at night, increased timeawake at night, increased latency to sleep onset, deviations fromproportions of time or duration of time in light sleep, deep sleepand/or REM sleep compared to those typically seen in individuals that donot experience insomnia, and the insomnia may produce a number ofeffects, such as not feeling well rested in the morning and/or duringthe day, decreased sleep satisfaction, increase in number of naps duringthe day, decreased wakefulness during daytime activities such as duringwork or school, or any combinations thereof.

In some embodiments, administering a subject in need of treatment for asleep disorder with an oral pulse-release dosage form of the presentdisclosure may provide effective treatment of one or more aspects of thesubject's sleep disorder.

For example, as described in Example 4, an example pulse-release dosageform comprising two example cannabinoid API's, THC and CBN providedeffective treatment of insomnia in a group of subjects. In particular,the subjects in the study described in Example 4 experienced insomnia,primarily or predominantly characterized by difficulty staying asleep atnight. Traditional sleep aids were marginally effective, and had aprofound impact on quality of sleep, and in particular REM and deepsleep components of their sleep experience. The example formulationprovided the subjects with longer sleep duration, and no deleteriouseffects on REM and deep sleep components of the sleep experience. Inaddition, surprisingly, the subjects experienced few residual effects(or “hangover”) of the treatment. This is in stark contrast to otherdrugs commonly used for sleep disorders

Surprisingly, the treatment did not affect all aspects of the subjects'sleep experience equally. For example, there was no effect on objectivemeasures of latency to sleep onset, number of awakenings during thenight, and no increase in time in REM sleep or deep sleep.

Recent studies indicate that individuals using cannabis expect it todecrease their sleep-related problems (Altman et al., 2019) and arelikely to reduce their use of sleep medications (Piper et al., 2017).Participants in the study by Altman and colleagues (2019) reported thatusing cannabis helped them fall asleep about 15 minutes faster and sleepfor about 2 hours longer. Nonetheless, previous studies have shown thatthe optimal concentration, dosage, timing, and route of administrationfor treating sleep disorders remain unknown (Babson et al., 2017).

Unexpectedly, as described in Example 5, and in contrast to the findingsdescribed in Example 4, administering subjects reporting difficulty infalling asleep with the same dosage of 10 mg THC and 5 mg CBN, butdelivered in an immediate release dosage form via the sublingual route,did not result in any objectively measured improvements in any aspect ofsleep. To the contrary, surprisingly, 10 mg THC and 5 mg CBN deliveredin an immediate release dosage form via the sublingual routesignificantly increased the time to fall asleep in these subjects.

Therefore, not all administration routes or dosage forms ofcannabinoids, or dosage timing, may be expected to be useful fortreating subjects experiencing insomnia. In addition, not all symptomsof insomnia may be effectively or equally treated by administering asubject with various formulations of cannabinoids.

Accordingly, the oral pulse-release compositions and dosage formsdescribed herein may provide particular advantages as compared to othermedications for treating sleep disorders.

In some embodiments, administering a subject in need of treatment for asleep disorder with an oral pulse-release dosage form of the presentdisclosure may result in an increase in the subject's total sleepingtime during the night.

In some embodiments, the administering may result in an increase in thesubject's total light sleeping time during the night.

In some embodiments, the administering may result in an increase in thesubject's light sleeping time as a proportion of total sleeping timeduring the night.

In some embodiments, the administering may result in an increase in thesubject's total time in bed during the night.

In some embodiments, the effects of the administering on the subject maybe measured using a SleepScore Max® system (e.g., see Example 4).

In some embodiments, the administering may result in an increase inSleepScore number as determined using a SleepScore Max® system.

In some embodiments, the administering may result in the subjectexperiencing an increase in feeling well rested in the morning and/orduring the day, perceived sleep quality, perceived total sleep timeduring the night, sleep satisfaction, or any combinations thereof. Theadministering may result in the subject experiencing a decrease inperceived frequency of awakenings during the night, number of times outof bed at night, number of naps during the day, or perceived time awakeat night, or any combinations thereof.

In some embodiments, the subject in need of treatment may beexperiencing insomnia that is primarily characterized by an inability tostay asleep during the night. In some embodiments, the insomnia may becharacterized using objective measurements, e.g. using a SleepScore Max®system. In some embodiments, characterization of the sleep disorder isreported by the subject, e.g. identified subjectively, or without usingobjective analysis e.g. using a SleepScore Max® system.

In some embodiments, the administering may not result in a decrease inlatency to sleep onset, an alteration of time in deep sleep and/or REMsleep, a hangover effect during the day after the administering, or anycombinations thereof.

In some embodiments, the administering may result in a decrease inlatency to sleep onset.

In some embodiments, the subject may have been previously beenadministered with one or more cannabinoids for treating a medicalcondition. For example, the subject may have previously used medicalmarijuana for one or more medical conditions.

The term “subject” as used herein refers to a warm blooded animal suchas a mammal which is treated for a condition that causes at least onesymptom. It is understood that at least humans, dogs, cats, and horsesare within the scope of the meaning of the term. In some embodiments,the subject is a human. In particular, the subject may be in need oftreatment for a sleep disorder, e.g. insomnia.

As used herein, the term “treat” or “treatment”, or a derivativethereof, contemplates partial or complete amelioration of at least onesymptom associated with the condition of the subject.

EXAMPLES

The present examples are provided for illustrative purposes only. Theyare not intended to and should not be interpreted to encompass the fullbreadth of the disclosure.

Example 1. Formulations of Example THC and CBN Oral Pulse-Release DosageForms

This Example provides example formulations of a pulse-release THC andCBN oral dosage forms of the present disclosure.

Example 1(a)

First pulse-release component THC 5 mg 5.7% CBN 2.5 mg 2.8%Microcrystalline Cellulose 65 mg 73.9% Hydroxypropylmethylcellulose 15mg 17.0% Magnesium stearate 0.5 mg 0.6% Total 88.0 mg 100.0% Secondpulse-release component THC 5 mg 3.8% CBN 2.5 mg 1.9% MicrocrystallineCellulose 95 mg 71.4% Methacrylic acid copolymer 30 mg 22.6% Magnesiumstearate 0.25 mg 0.2% Colloidal silicone dioxide 0.25 mg 0.2% Total133.0 mg 100.0%

Example 1(b)

First pulse-release component THC 5 mg 5.4% CBN 2.5 mg 2.7%Microcrystalline Cellulose 65 mg 70.7% Hydroxypropylmethylcellulose 10mg 10.8% Lactose 5 mg 5.4% Sodium starch glycolate 4 mg 4.3% Magnesiumstearate 0.5 mg 0.5% Total 92.0 mg 100.0% Second pulse-release componentTHC 5 mg 3.0% CBN 2.5 mg 1.5% Microcrystalline Cellulose 120 mg 71.1%Methacrylic acid copolymer 40 mg 23.7% Magnesium stearate 0.7 mg 0.4%Colloidal silicone dioxide 0.5 mg 0.3% Total 168.7 mg 100.0%

Example 1(c)

This is an example of a first pulse-release component that may becombined with any second pulse-release component described herein, e.g.may be combined with the second pulse-release component of Example 1(b)in some embodiments.

THC 3.27% 10 mg CBN 1.63% 5 mg Sugar Spheres 20.60% 63 mgMicrocrystalline cellulose 200 16.50% 50.5 mg Microcrystalline cellulose302 24.10% 73.7 mg Croscarmellose sodium 5.80% 17.7 mg Isomalt 24.20% 74mg FD&C Blue #2 0.30% 0.9 mg Silicone dioxide 0.50% 1.5 mg Magnesiumstearate 1.00% 3.1 mg Non-functional coating 2.10% 6.4 mg 100.00% 305.8mg

Example 1(d)

This is an example of a first pulse-release component that may becombined with any second pulse-release component described herein, e.g.may be combined with the second pulse-release component of Example 1(b)in some embodiments.

THC 3.27% 10 mg CBN 1.63% 5 mg Sugar Spheres 20.60% 63 mgMicrocrystalline cellulose 200 16.50% 50.5 mg Microcrystalline cellulose302 24.10% 73.7 mg Croscarmellose sodium 5.80% 17.7 mg Isomalt 24.20% 74mg FD&C Blue #2 0.30% 0.9 mg Silicone dioxide 0.50% 1.5 mg Magnesiumstearate 1.00% 3.1 mg Non-functional coating 2.10% 6.4 mg 100.00% 305.8mg

Example 1(e)

First pulse-release component THC 5 mg 4.6% CBN 2.5 mg 2.3% Lactose 85mg 78.7% Polyvinylpyrrolidone 10 mg 9.2% Polyvinylpolypyrrolidone 5 mg4.6% Magnesium stearate 0.5 mg 0.5% Total 108.0 mg 100.0% Secondpulse-release component THC 5 mg 3.8% CBN 2.5 mg 1.9% MicrocrystallineCellulose 95 mg 71.4% Methacrylic acid copolymer 30 mg 22.6% Magnesiumstearate 0.25 mg 0.2% Colloidal silicone dioxide 0.25 mg 0.2% Total133.0 mg 100.0%

Example 1(f)

First pulse-release component THC 10.0 mg 5.3% CBN 5.0 mg 2.7%Microcrystalline Cellulose 125.0 mg 66.8% Hydroxypropylmethylcellulose35.0 mg 18.7% Croscarmellose Sodium 11 mg 5.9% Magnesium stearate 1.2 mg0.6% Total 187.2 mg 100.0% Second pulse-release component THC 5 mg 3.8%CBN 2.5 mg 1.9% Microcrystalline Cellulose 95 mg 71.4% Methacrylic acidcopolymer 30 mg 22.6% Magnesium stearate 0.25 mg 0.2% Colloidal siliconedioxide 0.25 mg 0.2% Total 133.0 mg 100.0%

Example 1(g)

First pulse-release component THC 10.0 mg 5.3% CBN 5.0 mg 2.7%Microcrystalline Cellulose 125.0 mg 66.8% Hydroxypropylmethylcellulose35.0 mg 18.7% Croscarmellose Sodium 11 mg 5.9% Magnesium stearate 1.2 mg0.6% Total 187.2 mg 100.0% Second pulse-release component THC 10 mg 3.6%CBN 5 mg 1.8% Microcrystalline Cellulose 200 mg 71.2% Methacrylic acidcopolymer 65 mg 23.1% Magnesium stearate 0.5 mg 0.2% Colloidal siliconedioxide 0.5 mg 0.2% Total 281.0 mg 100.0%

Example 1(h)

First pulse-release component THC 10.0 mg 5.3% CBN 5.0 mg 2.7%Microcrystalline Cellulose 125.0 mg 66.8% Hydroxypropylmethylcellulose35.0 mg 18.7% Croscarmellose Sodium 11 mg 5.9% Magnesium stearate 1.2 mg0.6% Total 187.2 mg 100.0% Second pulse-release component THC 20.0 mg6.1% CBN 10.0 mg 3.0% Microcrystalline Cellulose 225.0 mg 68.3%Methacrylic acid copolymer 72.0 mg 21.9% Magnesium stearate 1.5 mg 0.5%Colloidal silicone dioxide 0.75 mg 0.2% Total 329.3 mg 100.0%

Example 1(i)

First pulse-release component THC 5.0 mg 5.3% CBN 10.0 mg 2.7%Microcrystalline Cellulose 125.0 mg 66.8% Croscarmellose Sodium 11 mg5.9% Magnesium stearate 1.2 mg 0.6% Total 187.2 mg 100.0% Secondpulse-release component THC 5.0 mg 3.8% CBN 10.0 mg 1.9%Microcrystalline Cellulose 215.0 mg 71.4% Hydroxypropylmethylcelluloseacetate 57.0 mg 22.6% Magnesium stearate 1.5 mg 0.2% Colloidal siliconedioxide 0.75 mg 0.2% Total 289.25 mg 100.0%

Example 1(j)

First pulse-release component THC 10.0 mg 4.7% CBN 10.0 mg 4.7%Microcrystalline Cellulose 135.0 mg 63.2% Hydroxypropylmethylcellulose41.3 mg 19.3% Croscarmellose Sodium 16 mg 7.5% Magnesium stearate 1.2 mg0.6% Total 213.5 mg 100.0% Second pulse-release component THC 5.0 mg2.7% CBN 10.0 mg 5.4% Microcrystalline Cellulose 125.0 mg 70.0%Methacrylic acid copolymer 43.0 mg 23.4% Magnesium stearate 0.6 mg 0.3%Colloidal silicone dioxide 0.3 mg 0.2% Total 183.9 mg 100.0%

Example 1(k)

First pulse-release component THC 10.0 mg 4.7% CBN 10.0 mg 4.7%Microcrystalline Cellulose 135.0 mg 63.2% Hydroxypropylmethylcellulose41.3 mg 19.3% Croscarmellose Sodium 16 mg 7.5% Magnesium stearate 1.2 mg0.6% Total 213.5 mg 100.0% Second pulse-release component THC 5.0 mg2.7% CBN 10.0 mg 5.4% Microcrystalline Cellulose 125.0 mg 70.0%Cellulose Acteate Pthalate 43.0 mg 23.4% Magnesium stearate 0.6 mg 0.3%Third pulse-release component THC 5.0 mg 2.7% CBN 10.0 mg 5.4%Microcrystalline Cellulose 125.0 mg 70.0% Methacrylic acid copolymer43.0 mg 23.4% Magnesium stearate 0.6 mg 0.3%

Example 1(1)

First pulse-release component THC 2.5 mg 1.3% CBN 1.25 mg 0.6%Microcrystalline Cellulose 135.0 mg 68.4% Hydroxypropylmethylcellulose41.3 mg 20.9% Croscarmellose Sodium 16 mg 8.1% Magnesium stearate 1.2 mg0.6% Total 197.25 mg 100.0% Second pulse-release component THC 2.5 mg1.4% CBN 1.25 mg 0.7% Microcrystalline Cellulose 125.0 mg 72.4%Methacrylic acid copolymer 43.0 mg 24.9% Magnesium stearate 0.6 mg 0.3%Colloidal silicone dioxide 0.3 mg 0.2% Total 172.65 mg 100.0%

Example 1(m)

First pulse-release component THC 3.0 mg 1.5% CBN 1.5 mg 0.8%Microcrystalline Cellulose 135.0 mg 68.2% Hydroxypropylmethylcellulose41.3 mg 20.9% Croscarmellose Sodium 16.0 mg 8.1% Magnesium stearate 1.2mg 0.6% Total 198.0 mg 100.0% Second pulse-release component THC 3.0 mg1.7% CBN 1.5 mg 0.9% Microcrystalline Cellulose 125.0 mg 72.1%Methacrylic acid copolymer 43.0 mg 24.8% Magnesium stearate 0.6 mg 0.3%Colloidal silicone dioxide 0.3 mg 0.2% Total 173.4 mg 100.0%

Example 1(n)

First pulse-release component THC 4.0 mg 2.0% CBN 2.0 mg 1.0%Microcrystalline Cellulose 135.0 mg 67.7% Hydroxypropylmethylcellulose41.3 mg 20.7% Croscarmellose Sodium 16 mg 8.0% Magnesium stearate 1.2 mg0.6% Total 199.5 mg 100.0% Second pulse-release component THC 4.0 mg2.3% CBN 2.0 mg 1.1% Microcrystalline Cellulose 125.0 mg 71.5%Methacrylic acid copolymer 43.0 mg 24.6% Magnesium stearate 0.6 mg 0.3%Colloidal silicone dioxide 0.3 mg 0.2% Total 174.9 mg 100.0%

Example 1(o)

First pulse-release component THC 0.5 mg 0.3% CBN 5.0 mg 2.5%Microcrystalline Cellulose 135.0 mg 67.8% Hydroxypropylmethylcellulose41.3 mg 20.8% Croscarmellose Sodium 16 mg 8.0% Magnesium stearate 1.2 mg0.6% Total 199.0 mg 100.0% Second pulse-release component THC 0.5 mg0.3% CBN 5.0 mg 2.9% Microcrystalline Cellulose 125.0 mg 71.7%Methacrylic acid copolymer 43.0 mg 24.7% Magnesium stearate 0.6 mg 0.3%Colloidal silicone dioxide 0.3 mg 0.2% Total 174.4 mg 100.0%

Example 1(p)

First pulse-release component THC 1.0 mg 0.5% CBN 10.0 mg 4.9%Microcrystalline Cellulose 135.0 mg 66.0% Hydroxypropylmethylcellulose41.3 mg 20.2% Croscarmellose Sodium 16 mg 7.8% Magnesium stearate 1.2 mg0.6% Total 204.5 mg 100.0% Second pulse-release component THC 1.0 mg0.6% CBN 10.0 mg 5.6% Microcrystalline Cellulose 125.0 mg 69.5%Methacrylic acid copolymer 43.0 mg 23.9% Magnesium stearate 0.6 mg 0.3%Colloidal silicone dioxide 0.3 mg 0.2% Total 179.9 mg 100.0%

Example 1(q)

First pulse-release component THC 2.0 mg 0.9% CBN 20.0 mg 9.3%Microcrystalline Cellulose 135.0 mg 62.6% Hydroxypropylmethylcellulose41.3 mg 19.2% Croscarmellose Sodium 16 mg 7.4% Magnesium stearate 1.2 mg0.6% Total 215.5 mg 100.0% Second pulse-release component THC 2.0 mg1.0% CBN 20.0 mg 10.5% Microcrystalline Cellulose 125.0 mg 65.5%Methacrylic acid copolymer 43.0 mg 22.5% Magnesium stearate 0.6 mg 0.3%Colloidal silicone dioxide 0.3 mg 0.2% Total 190.9 mg 100.0%

Example 2. Formulation of an Example Oral Pulsatile Dosage Form of THCand CBN

This Example describes a method of formulating an example 2-pulse oraldosage form of THC and CBN. For example, example THC and CBN oral dosageforms of Example 1 (e.g., Examples 1a, 1b, 1c, 1d, 1e and 1f, amongothers described herein) may in some embodiments be formulated accordingto the methods described in Example 2. In this example, the THC and CBNis formulated in a 50:50 ratio of immediate release (“IR THC+CBN”, forrelease in pulse 1): extended release (“ER THC+CBN”, for release inpulse 2).

Dispensing and Raw Material Preparation

(a) Preparation of Coating Suspension:

Weigh VIVACOAT Protect E into an appropriately sized container. Weigh 60mL Ethanol into a suitably sized beaker equipped with a magnetic stirbar. Place beaker with Ethanol onto the magnetic stir plate and beginmixing vigorously without splashing. Slowly add the VIVACOAT Protect Eto the Ethanol while stirring. Stir speed may be adjusted as needed.

(b) Preparation of the Oil Containing the THC and CBN:

Heat an amount of oil sufficient to contain the desired amount of THCand CBN (e.g., about 30 mL to 120 mL) in an oven at 90° C. to lower theviscosity.

-   -   (i) Preparation of ER THC+CBN oil:

Weigh half of the oil containing THC and CBN into a beaker with amagnetic stir bar—this half of the oil will be the ER THC+CBN oil. Placebeaker on magnetic stir plate and begin spinning. Weigh out the Ethanol(approximately 60 mL) and add it to the ER THC+CBN oil. Some stirringwith a spatula may be required for the stir bar to spin freely. Adjustspeed of the magnetic stirrer to maintain good mixing.

-   -   (ii) Preparation of IR THC+CBN oil:

Move the remaining half of the oil containing THC and CBN to a magneticstir plate with a stir bar and begin stirring—this half of the oil willbe the IR THC+CBN oil. Weigh out the Ethanol (approximately 60 mL) andadd it to the IR THC+CBN oil. Some stirring with a spatula may berequired for the stir bar to spin freely. Adjust speed of the magneticstirrer to maintain good mixing.

-   -   (c) Preparation of the substrate and microcrystalline cellulose        LP200:

Weigh out a first aliquot of 1,000 g of substrate (e.g., sugar spheres)and load into the bowl of a planetary mixer. Weigh out a second aliquotof 1,000 g of substrate into a separate container and set aside. Weigh afirst portion of 600 g of microcrystalline cellulose LP200 into acontainer. Weigh a second portion of 600 g of microcrystalline celluloseLP200 in a separate container. Weigh a third portion of 400 g ofmicrocrystalline cellulose LP200 in a separate container.

Plating and Coating

(a) Preparation of ER THC+CBN Powder:

Begin mixing the first aliquot of the substrate in the mixer at lowspeed. Slowly add the ER THC+CBN oil into the substrate while mixing.Maintain a slow consistent pour until all ER THC+CBN oil has been added.Use some extra Ethanol to rinse any residual oil from the beaker and addto the substrate. Slowly add the first portion of microcrystallinecellulose LP200 to the mixer. Stir well until combined, stopping whenneeded to break up clumps. Ensure all the ER THC+CBN oil is incorporatedinto substrate and microcrystalline cellulose LP200. Continue slowlymixing and slowly add the VIVACOAT Protect E/Ethanol coating suspension.Maintain a slow consistent pour until all coating suspension has beenadded. Slowly add the 400 g portion of microcrystalline cellulose LP200to the mixing bowl while mixing at slow speed. Stir well until combined,stopping when needed to break up clumps. Empty mixer contents onto abaking sheet and spread out for drying.

(b) Preparation of IR THC+CBN Powder:

Begin mixing second aliquot of substrate in the mixer at low speed.Slowly add the IR THC+CBN oil into the substrate while mixing. Maintaina slow consistent pour until all the IR THC+CBN oil has been added. Usesome extra Ethanol to rinse any residual oil from the beaker and add tothe substrate. Slowly add the remaining microcrystalline cellulose LP200to the mixer. Stir well until combined, stopping when needed to break upclumps. Ensure all the IR THC+CBN oil is incorporated into substrate andmicrocrystalline cellulose LP200. Empty mixer contents onto a bakingsheet and spread out for drying.

Powder Drying

Dry the ER and IR powders under high vacuum with no heat for ˜3 hours oruntil dry. If a vacuum environment is not available, place trays on abaker's rack and set in a low humidity (RH 45%) room overnight. Retrievetrays with dried powder. Keep ER and IR powders separate until theblending step (below). Break up clumps by hand or with a mortar andpestle. Sieve the powders separately through a #20 mesh screen. If notblending right away, double bag the powders separately and seal with adesiccant pack in the outer bag.

Blending

Load the ER and IR powder into a V-Blender. Weigh microcrystallinecellulose M302 and add it to the V-Blender. Weigh Isomalt and add it tothe V-Blender. Weigh croscarmellose sodium and add it to the V-Blender.Blend the mixture at top speed for 2 minutes. Weigh and sieve blue dyethrough a #20 mesh screen. Add the blue dye by making a shallow pocketin the center of the powder, adding the blue dye, and filling the pocketwith the powder blend. Blend mixture for 12 minutes. Weigh and sievemagnesium stearate through a #20 mesh screen. Add the magnesium stearateto the blend in the same manner as the blue dye. Blend mixture for 2minutes. Discharge blend slowly into a poly bag. Double bag withdesiccant pack in the outer bag.

Tableting

Load the powdered blend into the hopper of an Elizabeth EP 200 tabletpress. Begin batch compression utilizing the following parameters:tablet tooling 9 mm round concave; tablet hardness 6-20 kp. Compress atthe target weight and collect tablets in an appropriately sizedcontainer.

Example 3—In Vitro Dissolution Testing

In vitro dissolution testing was performed on a 2-pulse oral dosage formof THC and CBN.

The in vitro dissolution testing was performed as follows:

The example pulse-release oral dosage form was placed in 0.1 N HCl fortwo hours, with sampling time points at 1, 1.5 and 2 hours, followed by8 hours in sodium phosphate buffer pH 6.8, at 37° C.±0.5° C., withsampling at 3, 3.5, 4, 5, 6, 7, 8, 9 and 10 hours.

THC concentration was measured using HPLC.

FIG. 1 is a graph reporting the in vitro dissolution release rate (g/mLper timepoint) of THC versus time in hours of an example 2-pulse oralpharmaceutical composition tablet. The immediate release component(providing pulse 1) began to be dissolved immediately, resulting in afirst time of peak release rate (PRR₁) after 1-2 hours. Dissolution ofthe delayed release component (pulse 2) provided a second time of peakrelease rate (PRR₂) after 3-4 hours.

FIG. 2 is a graph reporting the dissolution profile of cumulativerelease of % total THC dose versus time in hours of the example 2-pulseoral pharmaceutical composition tablet. 50% of the total dose of the THCAPI was released after about 2 hours, and 90% of the total dose of THCAPI was released after about 5 hours.

Example 4. Effects of a Tablet Combining THC with CBN on Staying Asleep

Cannabis as a sleep improvement solution has been receiving increasedattention, in light of the current legalization of cannabis for medicaluse in 33 states and Washington D.C. The influence of delta-9Tetrahydrocannabinol (THC) combined with cannabinol (CBN) on sleep ispreliminary, but pre-clinical research indicates that CBN may prolongsleep and be particularly effective when combined with othercannabinoids (Yoshida et al., 1995; Russo, 2011). The aim of the studyin this Example was to evaluate the impact of a combination of 10 mg THCand 5 mg CBN in a pulse-release tablet on the ability for participants(medical cannabis users) to stay asleep. The effect of the combinationtablet was evaluated using objectively measured and self-reported data.

SleepScore Max® (Consumer Sleep Solutions LLC, Delaware) was used tomeasure objective sleep, and self-report questionnaires were used tomeasure perceived sleep. The SleepScore Max® device uses Ultra-WidebandTechnology to track the subject's bodily gross and micro movements.SleepScore Max®, is a validated non-contact monitor designed tounobtrusively and objectively measure sleep at the user's home.

Objective data demonstrated that before using the combination tablet,participants slept 6 hours and 29 minutes on average, whereas during thecombination tablet use period participants slept 20 minutes longer (6hours and 49 minutes) on average (p<0.001; 5% improvement). Participantsreported a 22% improvement in feeling well-rested in the morning(p<0.0001), with an average rating of 53.32 before product use and arating of 65.21 during product use. Finally, participants reported an18% increase in overall sleep quality (p<0.0001), going from an averageof 57.36 before product use to 67.90 during product use.

This validation study found that the example dosage form combining THCwith CBN was associated with improved sleep in a sample of medicalcannabis users. This was demonstrated using both objective sleep datausing validated SleepScore® (Consumer Sleep Solutions LLC, Delaware)technology, and self-reported data.

The cultivation and use of the cannabis plant for its medicinal andindustrial benefits date back to ancient times. The use of cannabis as amethod to improve sleep has been receiving increased attention, in lightof the current legalization of cannabis for medical use in 33 states andWashington D.C. (NCSL, 2020). Recent studies indicate that individualsusing cannabis expect it to decrease their sleep-related problems(Altman et al., 2019) and are likely to reduce their use of sleepmedications (Piper et al., 2017). Participants in the study by Altmanand colleagues (2019) reported that using cannabis helped them fallasleep about 15 minutes faster and sleep for about 2 hours longer.However, further research is needed to understand the objective andperceived effects of cannabinoids on sleep.

Delta-9 tetrahydrocannabinol (THC) is one of the most widely studiedcannabinoids, but reviews of the scientific literature (Gates et al.,2014; Babson et al., 2017) document that its effects on sleep are notyet well understood. An early study by Cousens and DiMascio (1973) foundthat THC decreased time to fall asleep, measured objectively, but led toa “hangover” after-effect (i.e., continued effects, e.g. a continued“high” the following day). However, Chait (1990) found that THC was notassociated with hangover effects. Other early studies suggested that THCmight reduce REM sleep duration (Pivik et al., 1972; Feinberg et al.,1975) and increase deep sleep duration (Pivik et al., 1972; Barratt etal., 1974).

Recent research has benefited from a more sophisticated understanding ofTHC and sleep relative to earlier eras. Nonetheless, the optimalconcentration, dosage, timing, and route of administration remainunknown (Babson et al., 2017). Given these complexities and more, it hasbeen noted in the scientific literature that laboratory studies do notreflect people's naturalistic experiences of cannabis use and sleep(Bowles et al., 2017). The current study categorized sleep into fourcommonly known stages including light sleep, deep sleep, rapid eyemovement (REM), and wake.

Materials and Methods

Participants

Curio Wellness, LLC recruited medical cannabis patients, certified bythe Maryland Medical Cannabis Commission, who self-identified asexperiencing insomnia, in particular the subjects in this study feltthey had trouble staying asleep. Eligible participants were asked tovisit Curio Wellness dispensary in person on two occasions. During thesecond visit, they picked up the cannabis pulse-release dosage andreviewed the study instructions.

Forty-one people who met all eligibility criteria were recruited forparticipation. All participants signed an informed consent form prior tobeginning the study, informing them of potential risks and benefits aswell as other information about the voluntary study. Participants weregiven a $100 gift card upon completion of the study.

Design

A non-counterbalanced, pre-post study design was used. Aplacebo-controlled trial was preferred, however due to the State ofMaryland labeling requirements for medical cannabis products, this wasnot possible. Instead, the investigators decided a pre-product useperiod to establish sleep performance using SleepScore® would establisha baseline for comparison when treated with the pulse-release dosageform. Both quantitative and qualitative self-report data, as well asobjective sleep data, were collected. During the first visit, studyparticipants reviewed and signed informed consent, picked up theSleepScore Max® device, downloaded the research version of theSleepScore Max® companion app, and reviewed the study instructions. Theproduct was tested in-home, giving the advantage of providing insightinto the effectiveness of the product under real-life conditions andhence yielding more ecologically valid results.

An overview of the timeline is displayed in FIG. 3 . The pre-product useperiod consisted of 3 weeks during which participants were instructed totrack their sleep every night using SleepScore Max and complete a briefdaily questionnaire each morning. During this period, participants hadnot yet received the test product. The product use period consisted of 3weeks during which participants were asked to use the test product everynight, track their sleep with SleepScore Max every night, and complete abrief daily questionnaire each morning. In addition to the brief dailyquestionnaires that were sent each morning, participants were asked tocomplete three more in-depth sleep experience questionnaires. The firstof these sleep experience questionnaires was completed prior to productuse, the second was completed after 1 week of product use, and the thirdwas completed at the end of the study (after 3 weeks of product use).

Each study tablet contained 15 mg of total cannabinoids (10 mg of THC+5mg of CBN). These specific concentrations are commercially available tomedical cannabis users in Maryland and were chosen for the current studybased on previous research conducted by Curio Wellness. Tablets were apulse-release dosage form as described in Example 1(a).

Participants were instructed to swallow the tablet up to 30 minutesbefore bed, every night for 3 weeks. Participants were also asked todiscontinue use of any other medical cannabis products 3 hours beforegoing to bed, and to stop eating at least 2 hours before bed, during the3 weeks of the product use period.

Objective sleep data were collected using a SleepScore Max® system, anon-contact monitor designed to unobtrusively and objectively measuresleep at the user's home. SleepScore Max® provides standard annotated 30second epoch sleep stage data and commonly used sleep metrics such astime to fall asleep (sleep onset latency), number of awakenings, startand end of sleep sessions, and total sleep time. Time spent in lightsleep, deep sleep, and REM sleep (e.g. in minutes) together add up tototal sleep time. Wake after sleep onset describes the total number ofminutes a person is awake after falling asleep for the first time andbefore waking up prior to getting up. The total time in bed describesthe time between getting in and out of bed (from “lights out, starttracking session” to “lights on, stop tracking session” according to theSleepScore Max® app). With these measures, sleep efficiency and sleepmaintenance can be calculated. Sleep efficiency (in %) is calculated bydividing total sleep time by time in bed. Sleep efficiency of 85% andhigher is considered to reflect good sleep quality (Ohayon et al.,2017). Sleep maintenance (in %) describes the ability of staying asleeponce asleep, taking into account waking up too early (before getting outof bed) and/or struggling to get back to sleep (but not the time ittakes to fall asleep initially) and is calculated by dividing totalsleep time by the sum of the duration of all sleep stages, includingwake, after initially falling asleep. Also, all four relative stagedurations (% Light, % Deep, % REM, and % Wake) were calculated bydividing stage duration by the sum of the duration of all sleep stages,including wake, after initially falling asleep.

Validity of these sleep measurements has been shown multiple times, withgood performance compared to the gold standard sleep measurementtechnique of polysomnography (O'Hare et al., 2014; Zaffaroni et al.,2017; Schade et al., 2019; Zaffaroni et al., 2019). The SleepScore®technology can be compared to ultra-low energy radar. The sensitivity ofthe sensor and the performance of the signal processing algorithms allowthe detection of gross body movement and full respiration patterns bymeasuring the micro motion of the chest cavity.

SleepScore Max® provided three sleep scores: SleepScore®, Body Score,and Mind Score. These are normalized 100-point sleep quality scales,based on proprietary algorithms, using scientific averages for a user'sage and gender (Ohayon et al., 2004). SleepScore® is defined by sixsleep parameters (total sleep duration, time to fall asleep, time inlight sleep, time in deep sleep, time in REM, and number of awakeningsthroughout the night) and can be regarded as a general sleep qualityscale. Mind Score reflects the amount of REM sleep, which is known toplay an important role in creative thinking, problem solving, andemotional processing. Body Score reflects the amount of deep sleep,which is considered restorative sleep and is linked to the perception offeeling well-rested the next day.

Participants used the research version of the SleepScore Max® companionapp, called Max R. Max R is a slimmed down version of the publiclyavailable SleepScore Max® app, dedicated to serve as a sleep recordingdevice, and available for researchers at request. Max R sleep recordertracks sleep in the same way as the publicly available app, but it doesnot display sleep data and does not offer consumer features such as thesleep guide or smart alarm. It simply acts as a sleep tracker.

Brief daily questionnaires were sent each morning using Survey Monkey tocheck compliance with sleep tracking, check compliance with use of thepulse-release dosage during the product use period, and measureperceived sleep (e.g., “How long did you feel it took to fall asleeplast night?”). These brief daily questionnaires were administered duringthe entire 6-week study, both before and during product use.

Nightly objective sleep data and daily self-report data were analyzed inR (version 3.5.2) using multilevel regression analyses, taking intoaccount the nested structure of the data (nights within subjects). Analpha level of 0.05 was used. For the objective sleep data, analysescompared nights in the pre-product use period on which participantstracked their sleep to nights in the product use period on whichparticipants tracked their sleep and reported using the test product.For the daily self-report data, analyses compared nights in thepre-product use period on which participants provided responses tonights in the product use period on which participants providedresponses and reported using the test product.

MS Excel (version 1901, for Windows) was used to analyze thequantitative self-report sleep data from the sleep experiencequestionnaires. Descriptive statistics and one-tailed, paired-samplest-tests were conducted, using an alpha level of 0.05. Analyses comparedresponses to the sleep experience questionnaire administered beforeproduct use to the subsequent sleep experience questionnaires.

Results

Of the 41 participants who were recruited into the study, 1 did notregister a SleepScore Max® account and 2 chose to withdraw. Of those whowithdrew from the study, one cited a preexisting medical condition andthe other experienced technological difficulties. In addition, a fewindividuals remained in the study but did not provide complete data.Therefore, due to missing SleepScore Max® data, the objective sleepanalyses included 35 participants. Similarly, due to missing surveydata, the perceived sleep analyses included self-report data from 35participants.

Demographics

The average age of study participants was 47, ranging from 22 to 69. Thesample was 57% female. Over three-quarters (77%) described their race asWhite, and over half (54%) were married. The majority (57%) were workingfull-time, and 63% had finished college or earned graduate degrees.Annual household income ranged from less than $20,000 (3%) to $100,000or higher (40%).

At the beginning of the study, the most common medical conditions forwhich participants reported using cannabis were sleep/insomnia (69%),pain (40%), and generalized anxiety disorder (29%). Full resultssummarizing the medical conditions for which participants reported usingcannabis are shown in FIG. 4 .

Participants' sleep concerns during the weeks before product use areshown in FIG. 5 . The most common answer (83%) was waking up too oftenin the night, followed by not feeling well rested when waking up in themorning (74%). In addition, about one quarter (26%) reported taking toolong to fall asleep and waking up too early in the morning. The findingthat concerns about being able to stay asleep during the nightoutweighed concerns about being able to fall asleep confirms that theparticipants who were recruited for the current study were anappropriate match for the product being tested.

Participants were asked whether medical cannabis made them feel sleepy;89% replied yes and 11% replied no. They reported using a variety offorms of cannabis in the past to help with sleep. The most common formused was flower (49%). Full results summarizing forms of cannabis studyparticipants had used in the past to help with sleep are shown in FIG. 6.

Results of the objective sleep analyses are shown in Table 1. Theseresults revealed that treatment effects on parameters of wake aftersleep onset, number of awakenings, sleep efficiency, and sleepmaintenance were not significant. Nor was there a significant change intime to fall asleep. However, participants' average length of time inbed increased by 22 minutes (p<0.001; 5% improvement), leading to ahealthier amount of sleep. Before using the test product, studyparticipants slept 6 hours and 29 minutes on average, whereas during theproduct use period they slept 20 minutes longer (6 hours and 49 minutes)on average (p<0.001; 5% improvement). This increase in total sleep timetranslated into more light sleep, both in duration (p<0.001; 7%increase) and proportion of time (p=0.02). Taken together, these changesindicate improved sleep, reflected in a significant increase inSleepScore. Prior to using the test product, participants had an averageSleepScore of 78.98. While using the test product, average SleepScorerose to 80.21 (p=0.03; 2% increase), which is similar to the averageSleepScore for SleepScore Max® users in the same age group as the studysample. Objective sleep and multilevel regression results comparingnights before product use to nights during product use for n=35 (n=1020nights) are presented in Table 1.

TABLE 1 Objective Sleep Analyses Sleep Score: Baseline Treatment Effectvs. Baseline. Observed Pre-test Period Prod- Estimated (Base- uct Con-p- line) Use stant beta value SleepScore (0-100) 78.98 80.21 79.04 1.2320.033 BodyScore (0-100) 76.50 76.66 76.50 0.081 0.451 MindScore (0-100)78.18 79.87 78.26 1.479 0.055 Total Sleep 388.91 408.96 389.30 20.719<0.001 Time (minutes) Sleep Onset 21.58 24.94 21.58 2.655 0.051 Latency(minutes) Number of Awakenings 4.78 4.94 4.78 0.214 0.069 Wake AfterSleep 43.43 44.36 43.57 1.506 0.225 Onset (minutes) Time in Bed(minutes) 460.35 482.22 460.66 22.917 <0.001 Sleep Efficiency 84.2683.76 84.22 −0.396 0.256 Sleep Maintenance 84.43 84.41 84.40 −0.1540.396 Light (minutes) 240.49 256.36 240.75 17.003 <0.001 REM (minutes)76.58 79.74 76.79 2.474 0.096 Deep (minutes) 71.84 72.86 71.76 1.1700.241 % Light sleep 55% 56% 55% 0.983 0.018 % REM sleep 18% 17% 18%−0.276 0.234 % Deep sleep 17% 17% 17% −0.610 0.067 % Wake after sleeponset 10% 10% 10% −0.106 0.399

For pre-test period and the product use period, each average wascalculated by averaging nights across participants, and then averagingthose participants' averages to a single simple average, listed under“Observed” in the Table 1. Listed under “Estimated” in Table 1 are theoutcomes of the multilevel regression analyses. Regression model was asfollows: Sleepmeasureij=Const0ij+B*TestPeriodij; TestPeriod coded as 0for the observations during nights when participants were not using thepulse-release dosage, and 1 for nights when participants tracked theirsleep and reported using the pulse-release dosage. Nights during theproduct use period in which participants did not have objective data ordid not report using the pulse-release dosage were not included inanalyses.

Analyses of the daily self-report data suggested that the pulse-releasedosage helped participants experience better sleep. Analyses of thedaily self-report data suggested that the test product helpedparticipants experience better sleep. Participants perceived fewernighttime awakenings after falling asleep, going from 2.87 beforeproduct use to 2.33 during product use (p<0.0001; 19% decrease). Theyalso reported getting out of bed fewer times, from 1.21 before productuse to 0.95 during product use (p<0.0001; 21% decrease). In addition,participants reported a 22% improvement in feeling well-rested in themorning (p<0.0001), with an average rating of 53.32 before product useand a rating of 65.21 during product use. Participants reported a 18%increase in overall sleep quality (p<0.0001), going from an average of57.36 before product use to 67.90 during product use. See Table 2.

TABLE 2 Self-report daily questionnaire and multilevel regressionresults comparing nights before product use to nights during product usefor n = 35 (n = 1236 nights). Observed Pre- Prod- Estimated test uctCon- p- Period Use stant beta value Bedtime Sleepiness (0-100) 65.7167.02 65.74 1.293 0.103 Time to Fall Asleep (minutes) 24.58 24.25 24.370.059 0.482 Number of Awakenings 2.87 2.33 2.86 −0.531 <0.0001 Number ofTimes Out of Bed 1.21 0.95 1.21 −0.256 <0.0001 Well-rested in the 53.3265.21 53.38 11.922 <0.0001 Morning (0-100) Sleep Quality (0-100) 57.3667.90 57.43 10.59 <0.0001

For pre-test period and the product use period, each average wascalculated by averaging nights across participants, and then averagingthose participants' averages to a single simple average, listed under“Observed” in Table 2.

Overall, study participants reported feeling more satisfied with theirsleep and felt better in the morning. Before using the product, theywoke up feeling rested only 2 mornings per week. By the end of thestudy, this had increased to 4 mornings per week. They reported nappingless often during the day, presumably because they were sleeping muchbetter at night. These effects all were shown after 1 week of using theproduct and were sustained through the end of the study (3 weeks ofproduct use).

The results of the daily questionnaires were confirmed by significantsleep improvements that were observed when comparing the sleepexperience questionnaires. The first of these sleep experiencequestionnaires was completed before the product use period, the secondwas completed after 1 week of product use, and the third was completedat the end of the study (after 3 weeks of product use). First, to testfor a 1-week effect, we compared participants' perceptions of theirsleep after 1 week of using the product to how they perceived theirsleep before using the product. Significant improvements were found fornumber of awakenings, time awake during the night after falling asleep,total sleep time, feeling well-rested in the morning, overall sleepsatisfaction, and frequency of daytime napping. Next, to test for a3-week effect, participants' perceptions of their sleep at the end ofthe study were compared to how they perceived their sleep before usingthe product. All significant effects noted at 1 week were sustained at 3weeks: number of awakenings, time awake during the night after fallingasleep, total sleep time, feeling well-rested in the morning, overallsleep satisfaction, and frequency of daytime napping. Details arepresented in FIG. 7 to FIG. 12 .

As shown in FIG. 7 , participants felt they woke up less often duringthe product use period. Before using the product, they reported wakingup 3 times per night on average. This decreased to 2 times per nightafter 1 week of using the product (p=0.009) and stayed at 2 times pernight after 3 weeks of using the product (p=0.007). As shown in FIG. 8 ,participants felt they spent less time awake at night (after fallingasleep initially) during the product use period. There was a 26-minutedecrease in perceived amount of time awake after 1 week of using theproduct (p=0.005). After 3 weeks of product use, there was a 14-minutedecrease compared to when participants were not using the product(p=0.03). As shown in FIG. 9 , participants felt they slept more duringthe product use period. There was a 37-minute increase in perceivednightly total sleep time after 1 week of using the product (p<0.001).After 3 weeks of product use, there was a 35-minute increase compared towhen participants were not using the product (p<0.001). As shown in FIG.10 , participants felt more well rested upon waking in the morningduring the product use period. Before using the product, they woke upfeeling rested only 2 mornings per week. This increased to 3 morningsper week after 1 week of product use (p<0.001) and 4 mornings per weekafter 3 weeks of product use (p<0.001). As shown in FIG. 11 ,participants were more satisfied with their sleep during the product useperiod. Before using the product, they reported feeling satisfied 3nights per week. This increased to 4 nights per week after 1 week ofproduct use (p=0.003) and remained at 4 nights per week after 3 weeks ofproduct use (p=0.004). As shown in FIG. 12 , participants reduced theirfrequency of taking daytime naps during the product use period. Beforeusing the product, they reported napping 3 days per week. This decreasedto only 1 day per week after 1 week of product use (p<0.001) andcontinued to be only 1 day per week after 3 weeks of product use(p<0.001). Due to the State of Maryland labeling requirements formedical cannabis products, a placebo controlled trial was not possibleregarding the conduct of this study.

The timing of this study unexpectedly coincided with the COVID-19pandemic. Given that the study design did not include a control group,the extent to which the effects were caused by the cannabispulse-release dosage versus health and lifestyle changes associated withthe COVID-19 pandemic cannot be fully known. Data collection occurredfrom February 24 to April 5. Maryland's stay-at-home directive was notordered until Mar. 30, 2020 (Wenger & Wood, 2020), but closures ofnon-essential business, school closings, and other restrictions beganearlier (Dance, 2020). The increase in total sleep time found in thecurrent study sample is in the same direction as national SleepScore®data from Mar. 16-Apr. 3, 2020, showing that, on average, people in theUnited States spent more time in bed and slept longer during COVID-19restrictions compared to before (SleepScore Labs, 2020).

DISCUSSION

In summary, the validation study in this Example evaluated theeffectiveness of a pulse-release oral dosage form product combining THCwith CBN to improve ability to stay asleep. Medical cannabis patientscertified by the Maryland Medical Cannabis Commission who felt they hadtrouble staying asleep were recruited by Curio Wellness into the study.The research participants tracked their sleep for 3 weeks and thentested the product for 3 weeks in their own homes while continuing totrack their sleep. This way of testing has the advantage of providinginsight into the effectiveness of the product under real-life conditionsand hence yielding more ecologically valid results.

The tablets were administered as a pulse-release dosage form: the dosageform was designed so that half of the dosage was released immediatelyafter oral administration, and the remaining half was released 2-3 hourslater. The study in this Example found that an example product combiningTHC with CBN was directly associated with both improved objective andperceived sleep quality and duration in a sample of medical cannabisusers.

Example 5. Effects of a Tablet Combining THC with CBN on Falling Asleep

This Example describes a study evaluating the impact of a combination of10 mg THC and 5 mg CBN in an immediate-release sublingual tablet on theability for participants (medical cannabis users) to fall asleep. Theeffect of the combination tablet was evaluated using objectivelymeasured and self-reported data.

The combination cannabinoid tablet was tested in 28 medical cannabispatients certified by the Maryland Medical Cannabis Commission who feltthey had trouble falling asleep, covering 445 nights of use of theproduct.

Analysis of the objective sleep data indicated that use of the fallingasleep tablet was unexpectedly associated with a statisticallysignificant increase in how long it took to fall asleep. Participants'average sleep onset latency slightly rose from 24 minutes withoutintervention to 26 minutes when using the falling asleep tablet. Inaddition to the effect on falling asleep, the objective sleep data alsoshowed small but significant declines in sleep efficiency (−1%) andsleep maintenance (−1%), both outcome measures reflecting the ability tospend time in bed asleep rather than awake.

Mirroring the objective data, the self-report data did not showimprovement in how many minutes participants felt it took them to fallasleep. Perceived sleep onset did not change significantly across thedaily questionnaires or the three sleep experience questionnaires.However, there was significant improvement in how often participantsfelt that they fell asleep within their preferred amount of time, goingfrom an average of 3 nights per week to 4 nights per week.

Despite the lack of improvement in falling asleep faster, participantsreported that the product helped their sleep in many other ways. At theend of the study, they felt sleepier at bedtime, felt more rested in themorning, and were more satisfied with their sleep, compared to the weeksbefore using the test product. They also felt they woke up less oftenand got out of bed less often during the night. In addition,participants reported a significant decrease in how often feelings ofsleepiness affected their school, work, or private life.

Materials and Methods

Participants

Curio Wellness recruited medical cannabis patients, certified by theMaryland Medical Cannabis Commission, who self-identified asexperiencing insomnia, in particular the subjects in this study feltthey had trouble falling asleep. Curio Wellness obtained informedconsent from all participants and provided them with the cannabis testproduct, a SleepScore Max® device, a guide for using the researchversion of the SleepScore Max® companion app, and additional studyinstructions.

To be considered for participation, the medical cannabis patients had tobe at least 21 years old and willing to track their sleep every nightfor 6 weeks. They also had to be willing to use the test product everynight for 3 weeks, and willing to discontinue other cannabis use atleast 3 hours before bed during the product use period.

In order to test the product in a sample of otherwise healthy users,people with other sleep disorders (e.g., narcolepsy, restless legsyndrome, sleep apnea) or psychological disorders affecting sleep (e.g.,clinical depression, bipolar disorder, schizophrenia) were excluded.People taking sleep medications (prescription or over-the-counter) oranti-convulsant medications were excluded, as were people who typicallyhad 3 or more alcoholic beverages on 4 or more nights per week. Womenwho were pregnant, lactating, or planning to become pregnant in the next2 months were excluded. Other exclusion criteria included being a shiftworker, having a child at home under 12 months old, or planning totravel across multiple time zones or be away from home for more than 5days during the entire study.

35 people who met all eligibility criteria were recruited forparticipation. All participants signed an informed consent form prior tobeginning the study, informing them of potential risks and benefits aswell as other information about the voluntary study. Participants weregiven a $100 gift card upon completion of the study.

Study Design

A non-counterbalanced, pre-post study design was implemented.Participants were aware of the sleep benefit of the intervention. Bothquantitative and qualitative self-report data, as well as objectivesleep data, were collected. The data collection period of the study wasexecuted from March 23-May 3, 2020. The product was tested in-home,giving the advantage of providing insight into the effectiveness of theproduct under real-life conditions and hence yielding more ecologicallyvalid results. An overview of the timeline is displayed in FIG. 13

The pre-product use period consisted of 3 weeks during whichparticipants were instructed to track their sleep every night usingSleepScore Max® and complete a brief daily questionnaire each morning.During this period, participants had not yet received the test product.

The product use period consisted of 3 weeks during which participantswere asked to use the test product every night, track their sleep withSleepScore Max® sleep measurement system every night, and complete abrief daily questionnaire each morning.

In addition to the brief daily questionnaires that were sent eachmorning, participants were asked to complete 3 longer surveys. The firstof these sleep experience questionnaires was completed prior to productuse, the second was completed after 1 week of product use, and the thirdwas completed at the end of the study (after 3 weeks of product use).

Procedures

Participants were provided with instructions on how to set up and useSleepScore Max® and the companion app. Detailed instructions for usingthe test product were reviewed with each participant by a Curio Wellnessstudy staff member. Participants were asked to discontinue use of anyother medical cannabis products 3 hours before going to bed, and to stopeating at least 2 hours before bed, during the 3 weeks of the productuse period. They were instructed to take 1 tablet 15 to 30 minutesbefore bed, every night for 3 weeks.

Cannabis Test Product

Each tablet contained 15 mg of total cannabinoids (10 mg of THC+5 mg ofCBN). These specific concentrations are commercially available tomedical cannabis users in Maryland and were chosen for the current studybased on previous research conducted by Curio Wellness. The tablet formwas dissolvable immediate release, and the delivery method wassublingual.

Measures

For this study, both objective and self-report sleep data werecollected.

Sleep Tracking

Objective sleep data were collected using SleepScore Max® as describedin Example 4.

Questionnaires

Self-report data were collected as described in Example 4.

Data Analyses

Data analyses were performed as described in Example 4.

Results

Of the 35 individuals who were recruited into the study, one withdrewdue to illness. Another participant reported technological difficulties,and some remained in the study but did not provide complete data.Therefore, due to missing SleepScore Max® data, the objective sleepanalyses included 28 participants. Similarly, due to missing surveydata, the perceived sleep analyses included self-report data from 26participants.

The 28 participants who consistently tracked their sleep did so for 79%of all nights in the study. There were 481 nights of tracked sleepbefore test product use and 445 nights during which participants usedthe test product and tracked their sleep (76% compliance rate for bothactivities during product use).

Across the sample of 28 participants who consistently provided dailyself-report data, there were 982 daily questionnaire responses (84%response rate). Participants reported using the test product for 86% ofnights during the product use period (but did not track their sleep onall of those nights). For the nights participants reported not using thetest product, they stated reasons such as not sleeping at home thatnight, worry about not waking up on time the next morning, and having acold. No one reported taking more than the recommended dose.

According to SleepScore Max® user registration data, the average age was41, ranging from 24 to 71. Based on data collected in the first sleepexperience questionnaire, 65% were female, 84% described their race asWhite, and over half (54%) were married. The majority (53%) were workingfull-time, and 43% had finished college or earned graduate degrees.Annual household income ranged from less than $20,000 (4%) to $100,000or higher (34%).

At the beginning of the study, the most common medical conditions forwhich participants reported using cannabis were insomnia (73%),generalized anxiety disorder (50%), and pain (31%). Full results areshown in FIG. 14 .

The most common sleep concern during the weeks before starting to usethe falling asleep tablet was taking too long to fall asleep (92%),followed by not feeling well rested when waking up (85%) or throughoutthe day (77%). Full results are shown in FIG. 15 . The finding thatconcerns about falling asleep outweighed other types of sleep concernsconfirms that the participants who were recruited for the current studywere an appropriate match for the product being tested according totheir self-report.

Participants were asked whether medical cannabis made them feel sleepy;81% replied yes and 19% replied no. They reported using a variety offorms of cannabis in the past to help with sleep. The most common formused was flower (69%). Full results are shown in FIG. 16 .

Sleep Measured Objectively

Participants were recruited into the study based on self-reporteddifficulty falling asleep. Before product use, participants reportedtaking 37.50 minutes to fall asleep on average. However, objective sleepdata collected before product use showed that they actually fell asleepin 23.56 minutes on average. This length of sleep onset time is longerthan the average for SleepScore Max® users in the same age group as thestudy sample (20.58 minutes) but still within the range considered to benormal in the scientific and clinical sleep literature (less than 30minutes; Edinger et al., 2004; Ohayon et al., 2017). In the currentsample, during the period before using the product, on only 22% ofnights did the participants take 30 or more minutes to fall asleep.

Therefore, it appears that there may have been little room forimprovement in objective sleep onset in this sample.

Analysis of the objective sleep data indicated that the test product wasunexpectedly associated with a statistically significant increase in howlong it took to fall asleep (p=0.021). Before using the test product, asnoted above, participants had an average sleep onset latency of 23.56minutes. This average rose to 26.40 minutes during product use (12.05%increase). Related to the increased onset latency, a statisticallysignificant decrease in sleep efficiency during the product use period(p=0.029) going from 84.39% before product use to 83.34% during productuse (1.24% relative decrease) was observed. Similarly, sleep maintenancedecreased (p=0.047), going from 84.50% before product use to 83.64%during product use (1.02% relative decrease). Taken together, thesechanges indicate that participants had a harder time falling asleep andstaying asleep. See Table 3.

TABLE 3 Objective sleep and multilevel regression results comparingnights before product use to nights during product use for n = 28 (n =926 nights). Observed Pre- Prod- Estimated test uct Con- p- Period Usestant beta value SleepScore (0-100) 77.96 77.32 77.99 −0.552 0.190BodyScore (0-100) 75.74 76.03 75.73 0.419 0.272 MindScore (0-100) 77.4077.17 77.45 0.067 0.469 Total Sleep Time (minutes) 400.60 393.74 400.85−5.520 0.101 Sleep Onset 23.56 26.40 23.64 2.748 0.021 Latency (minutes)Number of Awakenings 4.86 4.92 4.87 0.038 0.396 Wake After Sleep 45.0346.85 44.88 1.903 0.175 Onset (minutes) Time in Bed (minutes) 475.24473.31 475.29 −0.077 0.493 Sleep Efficiency 84.39 83.34 84.34 −0.8870.029 Sleep Maintenance 84.50 83.64 84.47 −0.773 0.047 Light (minutes)250.11 246.71 250.28 −2.883 0.202 REM (minutes) 77.50 74.69 77.71 −2.5030.086 Deep (minutes) 72.99 72.34 72.86 −0.072 0.483 % Light Sleep 56%55% 56% −0.192 0.342 % REM Sleep 17% 17% 17% −0.466 0.100 % Deep Sleep17% 17% 17% 0.110 0.393 % Wake After Sleep Onset 10% 11% 10% 0.541 0.091

In Table 3, for pre-test period and the product use period, each averagewas calculated by averaging nights across participants, and thenaveraging those participants' averages to a single simple average,listed under “Observed” in Table 3. Listed under “Estimated” are theoutcomes of the multilevel regression analyses. Regression model was asfollows: Sleepmeasureij=Const0ij+B*TestPeriodij; TestPeriod coded as 0for the observations during nights when participants were not using thetest product, and 1 for nights when participants tracked their sleep andreported using the test product. Nights during the product use period inwhich participants did not have objective data or did not report usingthe test product were not included in analyses.

Given these surprising results, additional analyses were performed totest whether effects would be observed in specific subgroups. Ananalysis was conducted to determine whether objective sleep improvementoccurred in the subgroup of participants who began the study with thepoorest sleep onset latency (objectively measured, above the samplemedian of 19.80; n=14). This subgroup had the most need for a productthat could help them fall asleep faster and the most room forimprovement. However, the results were not significant. Another set ofanalyses was performed with males and females separately. No sleepimprovement was found for men or for women.

Sleep Measured by Daily Self-Report

Analyses of the daily self-report data found that the test producthelped participants feel that they experienced better sleep.Participants felt sleepier at bedtime, going from 59.73 before productuse to 65.93 during product use on a 0-100 scale (p<0.001; 10.38%increase). They perceived fewer nighttime awakenings after fallingasleep, going from 2.95 before product use to 2.27 during product use(p<0.001; 23.05% decrease). They also reported getting out of bed fewertimes, from 1.13 before product use to 0.97 during product use (p=0.01;14.16% decrease). In addition, participants reported a 23.19%improvement in feeling well-rested in the morning (p<0.001), with anaverage rating of 49.60 before product use and a rating of 61.10 duringproduct use on a 0-100 scale. Finally, participants reported a 18.31%increase in overall sleep quality (p<0.001), going from an average of54.30 before product use to 64.24 during product use on a 0-100 scale.However, there was no significant change for daily self-reported sleeponset. See Table 4.

TABLE 4 Self-report daily questionnaire and multilevel regressionresults comparing nights before product use to nights during product usefor n = 28 (n = 982 nights). Observed Pre- Prod- Estimated test uct Con-p- Period Use stant beta value Bedtime Sleepiness (0-100) 59.73 65.9360.02 5.684 <0.001 Sleep Onset 33.51 32.98 33.25 −0.137 0.472 Latency(minutes) Number of Awakenings 2.95 2.27 2.90 −0.621 <0.001 Number ofTimes Out of Bed 1.13 0.97 1.11 −0.133 0.010 Well-rested in the 49.6061.10 49.91 11.095 <0.001 Morning (0-100) Sleep Quality (0-100) 54.3064.24 54.79 9.044 <0.001

In Table 4, for pre-test period and the product use period, each averagewas calculated by averaging nights across participants, and thenaveraging those participants' averages to a single simple average,listed under “Observed” in Table 4. Listed under “Estimated” are theoutcomes of the multilevel regression analyses. Regression model was asfollows: Sleepmeasure_(ij)=Const_(0ij)+B*TestPeriod_(ij); TestPeriodcoded as 0 for the observations during nights when participants were notusing the test product, and 1 for nights when participants reportedusing the test product. Nights during the product use period in whichparticipants did not report using the product were not included inanalyses.

Sleep Measured by Sleep Experience Questionnaires

The results of the daily questionnaires were confirmed by significantsleep improvements that were observed when comparing the sleepexperience questionnaires. The first of these sleep experiencequestionnaires was completed before the product use period, the secondwas completed after 1 week of product use, and the third was completedat the end of the study (after 3 weeks of product use).

First, to test for a 1-week effect, we compared participants'perceptions after 1 week of using the product to the time before usingthe product. There was a significant reduction in how many days feelingsleepy or tired affected school, work, or private life (see FIG. 17 . Nosignificant changes were found for how many minutes it took to fallasleep or other aspects of perceived sleep.

Next, to test for a 3-week effect, participants' perceptions at the endof the study were compared to the time before using the product. Similarto the aforementioned 1-week effect, there was a reduction in how manydays feeling sleepy or tired affected participants' school, work, orprivate life (see FIG. 17 ). Participants reported improvements insleepiness at bedtime (FIG. 18 ) and how many days per week they wereable to fall asleep in their preferred amount of time (see FIG. 19 ),even though there was no significant change in how many minutes onaverage they reported it took to fall asleep (FIG. 20 ). In addition,there were significant improvements in feeling rested upon waking in themorning (see FIG. 21 ) and feeling satisfied with sleep (FIG. 22 ).

Discussion

This validation study evaluated the effectiveness of a product combiningTHC with CBN to help with falling asleep. Medical cannabis patientscertified by the Maryland Medical Cannabis Commission who felt they hadtrouble falling asleep were recruited by Curio Wellness into the study.The research participants tracked their sleep for 3 weeks and thentested the product for 3 weeks in their own homes while continuing totrack their sleep. This way of testing has the advantage of providinginsight into the effectiveness of the product under real-life conditionsand hence yielding more ecologically valid results.

SleepScore Max® was used to measure objective sleep, and self-reportquestionnaires were used to measure perceived sleep. In addition tobrief daily questionnaires that were sent each morning of the study tomeasure compliance and sleep experiences, participants completed 3longer surveys assessing perceived sleep and user experiences.

Across the 28 participants with consistent objective sleep data, therewere 481 nights of tracked sleep before test product use and 445 nightsduring which they tracked their sleep and reported using the testproduct (overall, 76% compliance rate for both activities during productuse).

Participants were recruited into the study based on self-reporteddifficulty falling asleep. Before using the product, they reportedtaking 38 minutes to fall asleep on average. However, objective sleepdata collected before product use showed that they actually were takingonly 24 minutes to fall asleep on average. Taking less than 30 minutesto fall asleep is considered normal in the scientific and clinical sleepliterature (Edinger et al., 2004; Ohayon et al., 2017). In the currentsample, during the period before using the product, on only 22% ofnights did the participants take 30 or more minutes to fall asleep.Therefore, it appears that there may have been little room forimprovement in objective sleep onset in this sample.

Analysis of the objective sleep data indicated that the test product wasunexpectedly associated with a statistically significant increase in howlong it took to fall asleep. Participants' average onset time rose from24 minutes before product use to 26 minutes during product use. Theobjective data also revealed that taking longer to fall asleep impactedsleep efficiency, meaning that participants spent less time asleep whilethey were in bed. Also, their ability to stay asleep was slightlynegatively affected, as indicated by a decrease in sleep maintenance.

Mirroring the objective data, the self-report data did not showstatistically significant improvement in how many minutes participantsfelt it took them to fall asleep. Perceived sleep onset did not changesignificantly across the daily questionnaires or the three sleepexperience questionnaires. However, at the end of the study there wassignificant improvement in how often participants felt that they fellasleep within their preferred amount of time, going from an average of 3nights per week to 4 nights per week.

Despite the lack of improvement in falling asleep faster, participantsreported that the product helped their sleep in many other ways. At theend of the study, they felt sleepier at bedtime, felt more rested in themorning, and were more satisfied with their sleep, compared to the weeksbefore using the test product. They also felt they woke up less oftenand got out of bed less often during the night. In addition,participants reported a significant decrease in how often feelings ofsleepiness affected their school, work, or private life.

When interpreting the study results, it must be considered that thetiming of this study unexpectedly coincided with the COVID-19 pandemic.Given that the study design did not include a control group, the extentto which the effects were caused by the cannabis test product versushealth and lifestyle changes associated with the COVID-19 pandemiccannot be fully known. Data collection occurred from March 23-May 3,2020. Maryland's stay-at-home directive was ordered on Mar. 30, 2020(Wenger & Wood, 2020), but closures of non-essential business, schoolclosings, and other restrictions began earlier (Dance, 2020).

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Unless otherwise required by context herein, singular terms shallinclude pluralities and plural terms shall include the singular.Singular forms “a”, “an” and “the”, and singular use of any word,include plural referents unless expressly and unequivocally limited onone referent.

It is understood the use of the alternative (e.g., “or”) herein is takento mean either one or both or any combination thereof of thealternatives. The term “and/or” used herein is to be taken mean specificdisclosure of each of the specified features or components with orwithout the other. For example, the term “and/or” as used in a phrasesuch as “A and/or B” herein is intended to include “A and B,” “A or B,”“A” (alone), and “B” (alone). Likewise, the term “and/or” as used in aphrase such as “A, B, and/or C” is intended to encompass each of thefollowing aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; Aand C; A and B; B and C; A (alone); B (alone); and C (alone).

As used herein, terms “comprising”, “including”, “having” and“containing”, and their grammatical variants, as used herein areintended to be non-limiting so that one item or multiple items in a listdo not exclude other items that can be substituted or added to thelisted items. It is understood that wherever aspects are describedherein with the language “comprising,” otherwise analogous aspectsdescribed in terms of “consisting of” and/or “consisting essentially of”are also provided.

As used herein, the term “about” refers to a value or composition thatis within an acceptable error range for the particular value orcomposition as determined by one of ordinary skill in the art, whichwill depend in part on how the value or composition is measured ordetermined, i.e., the limitations of the measurement system. Forexample, “about” or “approximately” can mean within one or more than onestandard deviation per the practice in the art. Alternatively, “about”or “approximately” can mean a range of up to 10% (i.e., ±10%) or moredepending on the limitations of the measurement system. For example,about 5 mg can include any number between 4.5 mg and 5.5 mg. Whenparticular values or compositions are provided in the instantdisclosure, unless otherwise stated, the meaning of “about” or“approximately” should be assumed to be within an acceptable error rangefor that particular value or composition.

The term “administering”, “administered” and grammatical variants refersto the physical introduction of an agent to a subject, using any of thevarious methods and delivery systems known to those skilled in the art.Exemplary routes of administration include intravenous, intramuscular,subcutaneous, intraperitoneal, spinal or other parenteral routes ofadministration, for example by injection or infusion. The phrase“parenteral administration” means modes of administration other thanenteral and topical administration, usually by injection, and includes,without limitation, intravenous, intramuscular, intraarterial,intrathecal, intralymphatic, intralesional, intracapsular, intraorbital,intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous,subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal,epidural and intrasternal injection and infusion, as well as in vivoelectroporation. Non-parenteral routes include oral, topical, epidermalor mucosal route of administration, for example, intranasally,vaginally, rectally, sublingually or topically. Administering can alsobe performed, for example, once, a plurality of times, and/or over oneor more extended periods.

Throughout this application various publications, patents, and/or patentapplications are referenced. The disclosures of the publications,patents and/or patent applications are hereby incorporated by referencein their entireties into this application in order to more fullydescribe the state of the art to which this disclosure pertains.

The above disclosure contains various examples of oral pulse-releasecompositions and dosage forms, and methods of treating sleep disordersin a subject by administering the oral pulse-release compositions anddosage forms. Aspects of these various examples may all be combined withone another, even if not expressly combined in the present disclosure,unless they are clearly mutually exclusive.

The above disclosed subject matter is to be considered illustrative, andnot restrictive, and the appended claims are intended to cover all suchmodifications, enhancements, and other implementations which fall withinthe true spirit and scope of the present disclosure. Thus, to themaximum extent allowed by law, the scope of the present disclosure is tobe determined by the broadest permissible interpretation of thefollowing claims and their equivalents and shall not be restricted orlimited by the foregoing detailed description.

What is claimed is: 1-32. (canceled)
 33. A method of treating a sleepdisorder in a subject in need thereof, the method comprising:administering to the subject an oral pulse-release dosage formcomprising a total daily dose of a first cannabinoid activepharmaceutical ingredient (API₁) and a total daily dose of a secondcannabinoid API (API₂), wherein the oral pulse-release dosage formcomprises: a first pulse-release component (C₁) comprising a firstportion (P₁) of the first cannabinoid API (API₁P₁) and a first portion(P₁) of the second cannabinoid API (API₂P₁); and at least a secondpulse-release component (C₂) comprising a second portion (P₂) of thefirst cannabinoid API (API₁P₂) and a second portion (P₂) of the secondcannabinoid API (API₂P₂); wherein the total daily dose of each of theAPI₁ and the API₂ is divided between the first portion (P₁) in the firstpulse-release component (C₁) and at least the second portion (P₂) in theat least second pulse-release component (C₂); and wherein when thepulse-release dosage form is placed in an aqueous solution of 0.1N HClpH 1.1 for 2 hours followed by 8 hours in sodium phosphate buffer at pH6.8, at 37° C.±0.5° C., the pulse-release dosage form provides releaseof the API₁P₂ and the API₂P₂ beginning from 2 to 6 hours after releaseof the API₁P₁ and the API₂P₁ begins wherein: the first cannabinoid API(API₁) is delta-9-tetrahydrocannabinol (THC) and the second cannabinoidAPI (API₂) is cannabinol (CBN); the first pulse-release component (C₁)is an immediate release (IR) formulation of the first cannabinoid API(API₁) and the second cannabinoid API (API₂); the second pulse-releasecomponent (C₂) is a delayed release (DR) formulation of the firstcannabinoid API (API₁) and the second cannabinoid API (API₂); and foreach API, the first portion (P₁) is independently selected from 25% to75% of the total daily dose, and for each API the second portion (P₂) isindependently selected from 25% to 75% of the total daily dose.
 34. Themethod of claim 33, wherein: the administering results in an increase inthe subject's total sleeping time during the night.
 35. The method ofclaim 33, wherein: the administering results in an increase in thesubject's total light sleeping time during the night.
 36. The method ofclaim 33, wherein: the administering results in an increase in thesubject's light sleeping time as a proportion of total sleeping timeduring the night.
 37. The method of claim 33, wherein: the administeringresults in an increase in the subject's total time in bed during thenight.
 38. The method of claim 33, wherein: the administering results inan increase in the subject's total sleeping time during the night, anincrease in the subject's total light sleeping time during the night, anincrease in the subject's light sleeping time as a proportion of totalsleeping time during the night, an increase in the subject's total timein bed during the night, or any combination thereof, as measured by avalidated sleep monitoring device.
 39. The method of claim 33, whereinthe administering results in: the subject experiencing an increase inone or more of: feeling well rested in the morning and/or during theday; perceived sleep quality; perceived total sleep time during thenight; or sleep satisfaction; and/or the subject experiencing a decreasein one or more of: perceived frequency of awakenings during the night;number of times out of bed at night; number of naps during the day; orperceived time awake at night.
 40. The method of claim 33, wherein: thesleep disorder comprises insomnia, wherein the insomnia is primarilycharacterized by an inability to stay asleep during the night.
 41. Themethod of claim 40, wherein the insomnia is characterized using avalidated sleep monitoring device.
 42. The method of claim 40, whereincharacterization of the sleep disorder is reported by the subject. 43.The method of claim 33, wherein the administering does not result in: adecrease in latency to sleep onset; an alteration of time in deep sleepand/or REM sleep; and/or a hangover effect during the day after theadministering.
 44. The method of claim 33, wherein the subject haspreviously been administered with one or more cannabinoids for treatinga medical condition.
 45. The method of claim 33, wherein theadministering is up to 30 minutes, 1 hour, or 2 hours before the subjectintends to begin sleeping at night.
 46. The method of claim 33, whereinthe pulse-release dosage form provides a second time of peak releaserate (PRR₂) of each of the API₁ (PRR₂API₁) and the API₂ (PRR₂API₂) fromabout 2 to 6 hours after a first time of peak release rate (PRR₁). 47.The method of claim 46, wherein the PRR₁ is after 1-2 hours.
 48. Themethod of claim 33, wherein the total daily dose of the THC is from 1 mgto 40 mg and the total daily dose of the CBN is from 2.5 mg to 100 mg.49. The method of claim 33, wherein the total daily dose of the THC isselected from: at least 1 mg, at least 2 mg, at least 3 mg, at least 4mg, at least 5 mg, at least 6 mg, at least 8 mg, at least 10 mg, atleast 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, and atleast 35 mg, and the total daily dose of the CBN is selected from: atleast 2.5 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 15mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, andat least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg,at least 85 mg, at least 90 mg, and at least 95 mg.
 50. The method ofclaim 33, wherein: the first pulse-release component (C₁) comprises: thefirst portion (P₁) of the first cannabinoid API (API₁P₁) and the firstportion (P₁) of the second cannabinoid API (API₂P₁); one or morebinders; one or more disintegrants; one or more lubricants; and one ormore flow aids; and the second pulse-release component (C₂) comprises:the second portion (P₂) of the first cannabinoid API (API₁P₂) and thesecond portion (P₂) of the second cannabinoid API (API₂P₂); one or morebinders; one or more lubricants; and one or more flow aids; wherein thesecond pulse-release component is coated with a delayed-release layercomprising one or more pH-dependent and/or non-pH-dependent polymers,and optionally one or more plasticizers, one or more pore formers,and/or one or lubricants.
 51. The method of claim 50, wherein: in thefirst pulse-release component (C₁), the second pulse-release component(C₂), or both, when present: the binders comprise from 1 to 60% (w/w);the disintegrants comprise from 0.05 to 15% (w/w); the lubricantscomprise from 0.5 to 5% (w/w); the flow aids comprise from 0.05 to 0.5%(w/w); and the pH-dependent and/or non-pH-dependent polymers comprisefrom 0.5 to 35% (w/w).
 52. The method of claim 33, wherein: the firstpulse-release component (C₁) comprises: from 0.5 mg to 30 mg of thefirst cannabinoid active pharmaceutical ingredient (API₁); from 1.25 mgto 75 mg of the second cannabinoid active pharmaceutical ingredient; andmicrocrystalline cellulose, hydroxypropylmethylcellulose, and magnesiumstearate; and the second pulse-release component (C₂) comprises: from0.5 mg to 30 mg of the first cannabinoid active pharmaceuticalingredient (API₁); from 1.25 mg to 75 mg of the second cannabinoidactive pharmaceutical ingredient; and microcrystalline cellulose,methacrylic acid copolymer, magnesium stearate, and colloidal siliconedioxide.
 53. A method of treating a sleep disorder in a subject in needthereof, the method comprising: administering to the subject an oralpulse-release dosage form comprising a total daily dose of a firstcannabinoid active pharmaceutical ingredient (API₁) and a total dailydose of a second cannabinoid API (API₂), wherein the pulse-releasedosage form comprises: a first pulse-release component (C₁) comprising afirst portion (P₁) of the first cannabinoid API (API₁P₁) and a firstportion (P₁) of the second cannabinoid API (API₂P₁); a secondpulse-release component (C₂) comprising a second portion (P₂) of thefirst cannabinoid API (API₁P₂) and a second portion (P₂) of the secondcannabinoid API (API₂P₂); and at least a third pulse-release component(C₃) comprising a third portion (P₃) of the first cannabinoid API(API₁P₃) and a third portion (P₃) of the second cannabinoid API(API₂P₂); wherein the total daily dose of each of the API₁ and the API₂is divided between the first portion (P₁) in the first pulse-releasecomponent (C₁), the second portion (P₂) in the second pulse-releasecomponent (C₂), and at least the third portion (P₃) in the at leastthird pulse-release component (C₃); and wherein when the pulse-releasedosage form is placed in an aqueous solution of 0.1N HCl pH 1.1 for 2hours followed by 8 hours in sodium phosphate buffer at pH 6.8, at 37°C.±0.5° C., the pulse-release dosage form provides release of the API₁P₂and the API₂P₂ beginning from 1 to 4 hours after release of the API₁P₁and the API₂P₁ begins, and release of the API₁P₃ and the API₂P₃beginning from 1 to 4 hours after release of the API₁P₂ and the API₂P₂begins wherein: the first cannabinoid API (API₁) isdelta-9-tetrahydrocannabinol (THC) and the second cannabinoid API (API₂)is cannabinol (CBN); the first pulse-release component (C₁) is animmediate release (IR) formulation of the first cannabinoid API (API₁)and the second cannabinoid API (API₂); the second pulse-releasecomponent (C₂) is a delayed release (DR) formulation of the firstcannabinoid API (API₁) and the second cannabinoid API (API₂); and thethird pulse-release component (C₃) is a delayed release (DR) formulationof the first cannabinoid API (API₁) and the second cannabinoid API(API₂); and for each API, the first portion (P₁) is independentlyselected from 25% to 75% of the total daily dose, for each API, thesecond portion (P₂) is independently selected from 25% to 75% of thetotal daily dose, and, for each API, the third portion (P₃) isindependently selected from 25% to 75% of the total daily dose.
 54. Themethod of claim 53, wherein: the administering results in an increase inthe subject's total sleeping time during the night.
 55. The method ofclaim 53, wherein: the administering results in an increase in thesubject's total light sleeping time during the night.
 56. The method ofclaim 53, wherein: the administering results in an increase in thesubject's light sleeping time as a proportion of total sleeping timeduring the night.
 57. The method of claim 53, wherein: the administeringresults in an increase in the subject's total time in bed during thenight.
 58. The method of claim 53, wherein: the administering results inan increase in the subject's total sleeping time during the night, anincrease in the subject's total light sleeping time during the night, anincrease in the subject's light sleeping time as a proportion of totalsleeping time during the night, an increase in the subject's total timein bed during the night, or any combination thereof, as measured by avalidated sleep monitoring device.
 59. The method of claim 53, whereinthe administering results in: the subject experiencing an increase inone or more of: feeling well rested in the morning and/or during theday; perceived sleep quality; perceived total sleep time during thenight; or sleep satisfaction; and/or the subject experiencing a decreasein one or more of: perceived frequency of awakenings during the night;number of times out of bed at night; number of naps during the day; orperceived time awake at night.
 60. The method of claim 53, wherein: thesleep disorder comprises insomnia, wherein the insomnia is primarilycharacterized by an inability to stay asleep during the night.
 61. Themethod of claim 60, wherein the insomnia is characterized using avalidated sleep monitoring device.
 62. The method of claim 60, whereincharacterization of the sleep disorder is reported by the subject. 63.The method of claim 53, wherein the administering does not result in: adecrease in latency to sleep onset; an alteration of time in deep sleepand/or REM sleep; and/or a hangover effect during the day after theadministering.
 64. The method of claim 53, wherein the subject haspreviously been administered with one or more cannabinoids for treatinga medical condition.
 65. The method of claim 53, wherein theadministering is up to 30 minutes, 1 hour, or 2 hours before the subjectintends to begin sleeping at night.
 66. The method of claim 53, wherein:the pulse-release dosage form provides a second time of peak releaserate (PRR₂) of each of the API₁ (PRR₂API₁) and the API₂ (PRR₂API₂) fromabout 1 to 4 hours after a first PRR (PRR₁) and a third time of peakrelease rate (PRR₃) of each of the API₁ (PRR₃API₁) and the API₂(PRR₃API₂) from about 1 to 4 hours after the second time of PRR (PRR₂).67. The method of claim 66, wherein: the PRR₁ is after 1-2 hours. 68.The method of claim 53, wherein: the total daily dose of the THC is from10 mg to 40 mg and the total daily dose of the CBN is from 5 mg to 100mg.
 69. The method of claim 53, wherein: the total daily dose of the THCis selected from: at least 10 mg, at least 15 mg, at least 20 mg, atleast 25 mg, at least 30 mg, and at least 35 mg, and the total dailydose of the CBN is selected from: at least 5 mg, at least 10 mg, atleast 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35mg, and at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg,at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least80 mg, at least 85 mg, at least 90 mg, and at least 95 mg.
 70. Themethod of claim 53, wherein: the first pulse-release component (C₁)comprises: the first portion (P₁) of the first cannabinoid API (API₁P₁)and the first portion (P₁) of the second cannabinoid API (API₂P₁); oneor more binders; one or more disintegrants; one or more lubricants; andone or more flow aids; and the second pulse-release component (C₂)comprises: the second portion (P₂) of the first cannabinoid API (API₁P₂)and the second portion (P₂) of the second cannabinoid API (API₂P₂); oneor more binders; one or more lubricants; one or more flow aids; andwherein the second pulse-release component is coated with a firstdelayed-release layer comprising one or more pH-dependent and/ornon-pH-dependent polymers, and optionally one or more plasticizers, oneor more pore formers, and/or one or lubricants; and the thirdpulse-release component (C₃) comprises: the third portion (P₃) of thefirst cannabinoid API (API₁P₃) and the third portion (P₃) of the secondcannabinoid API (API₂P₃); one or more binders; one or more lubricants;and one or more flow aids; and wherein the third pulse-release componentis coated with a second delayed-release layer comprising one or morepH-dependent and/or non-pH-dependent polymers, and optionally one ormore plasticizers, one or more pore formers, and/or one or lubricants.71. The method of claim 70, wherein, in the first pulse-releasecomponent (C₁), the second pulse-release component (C₂), and/or thethird pulse-release component (C₃), when present: the binders comprisefrom 1 to 60% (w/w); the disintegrants comprise from 0.05 to 15% (w/w);the lubricants comprise from 0.5 to 5% (w/w); the flow aids comprisefrom 0.05 to 0.5% (w/w); and the pH-dependent and/or non-pH-dependentpolymers comprise from 0.5 to 35% (w/w).
 72. The method of claim 53,wherein: the first pulse-release component (C₁) comprises: from 2.5 mgto 30 mg of the first cannabinoid active pharmaceutical ingredient(API₁); from 1.25 mg to 75 mg of the second cannabinoid activepharmaceutical ingredient; and microcrystalline cellulose,hydroxypropylmethylcellulose, croscormellose sodium, and magnesiumstearate; the second pulse-release component (C₂) comprises: from 2.5 mgto 30 mg of the first cannabinoid active pharmaceutical ingredient(API₁); from 1.25 mg to 75 mg of the second cannabinoid activepharmaceutical ingredient; and microcrystalline cellulose, celluloseacetate phthalate, and magnesium stearate; and the third pulse-releasecomponent (C₃) comprises: from 2.5 mg to 30 mg of the first cannabinoidactive pharmaceutical ingredient (API₁); from 1.25 mg to 75 mg of thesecond cannabinoid active pharmaceutical ingredient; andmicrocrystalline cellulose, methacrylic acid copolymer, and magnesiumstearate.